2-Aminopyrimidine modulators of the histamine H4 receptor

ABSTRACT

2-Aminopyrimidine compounds are described, which are useful as H 4  receptor modulators. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H 4  receptor activity, such as allergy, asthma, autoimmune diseases, and pruritis.

This application is a divisional application of U.S. application Ser.No. 12/070,051, filed on Feb. 14, 2008, which claims the benefit of U.S.provisional patent application Ser. No. 60/889,798, filed on Feb. 14,2007, all of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to certain 2-aminopyrimidine compounds,pharmaceutical compositions containing them, methods of making them, andmethods of using them for the modulation of the histamine H₄ receptorand for the treatment of disease states, disorders, and conditionsmediated by histamine H₄ receptor activity.

BACKGROUND OF THE INVENTION

The histamine H₄ receptor (H₄R) is the most recently identified receptorfor histamine (for reviews, see: Fung-Leung, W.-P., et al., Curr. Opin.Invest. Drugs 2004, 5(11), 1174-1183; de Esch, I. J. P., et al., TrendsPharmacol. Sci. 2005, 26(9), 462-469; Zhang, M. et al. Pharmacol. Ther.2007, 113, 594-606; Thurmond, R. L. et al. Nat. Rev. Drug Disc. 2008, 7,41-53; Zhang, M. et al. Expert Opin. Investig. Drugs 2006, 15(11),1443-1452). The receptor is found in the bone marrow and spleen and isexpressed on eosinophils, basophils, mast cells (Liu, C., et al., Mol.Pharmacol. 2001, 59(3), 420-426; Morse, K. L., et al., J. Pharmacol.

Exp. Ther. 2001, 296(3), 1058-1066; Hofstra, C. L., et al., J.Pharmacol. Exp. Ther. 2003, 305(3), 1212-1221; Lippert, U., et al., J.Invest. Dermatol. 2004, 123(1), 116-123; Voehringer, D., et al.,Immunity 2004, 20(3), 267-277), CD8⁺ T cells (Gantner, F., et al., J.Pharmacol. Exp. Ther. 2002, 303(1), 300-307), dendritic cells, and humansynovial cells from rheumatoid arthritis patients (Ikawa, Y., et al.,Biol. Pharm. Bull. 2005, 28(10), 2016-2018). However, expression inneutrophils and monocytes is less well defined (Ling, P., et al., Br. J.Pharmacol. 2004, 142(1), 161-171). Receptor expression is at least inpart controlled by various inflammatory stimuli (Coge, F., et al.,Biochem. Biophys. Res. Commun. 2001, 284(2), 301-309; Morse, et al.,2001), thus supporting that H₄ receptor activation influencesinflammatory responses. Because of its preferential expression onimmunocompetent cells, the H₄ receptor is closely related with theregulatory functions of histamine during the immune response.

A biological activity of histamine in the context of immunology andautoimmune diseases is closely related with the allergic response andits deleterious effects, such as inflammation. Events that elicit theinflammatory response include physical stimulation (including trauma),chemical stimulation, infection, and invasion by a foreign body. Theinflammatory response is characterized by pain, increased temperature,redness, swelling, reduced function, or a combination of these.

Mast cell degranulation (exocytosis) releases histamine and leads to aninflammatory response that may be initially characterized by ahistamine-modulated wheal and flare reaction. A wide variety ofimmunological stimuli (e.g., allergens or antibodies) andnon-immunological (e.g., chemical) stimuli may cause the activation,recruitment, and de-granulation of mast cells. Mast cell activationinitiates allergic inflammatory responses, which in turn cause therecruitment of other effector cells that further contribute to theinflammatory response. It has been shown that histamine induceschemotaxis of mouse mast cells (Hofstra, et al., 2003). Chemotaxis doesnot occur using mast cells derived from H₄ receptor knockout mice.Furthermore, the response is blocked by an H₄-specific antagonist, butnot by H₁, H₂ or H₃ receptor antagonists (Hofstra, et al., 2003;Thurmond, R. L., et al., J. Pharmacol. Exp. Ther. 2004, 309(1),404-413). The in vivo migration of mast cells to histamine has also beeninvestigated and shown to be H₄ receptor dependent (Thurmond, et al.,2004). The migration of mast cells may play a role in allergic rhinitisand allergy where increases in mast cell number are found (Kirby, J. G.,et al., Am. Rev. Respir. Dis. 1987, 136(2), 379-383; Crimi,

E., et al., Am. Rev. Respir. Dis. 1991, 144(6), 1282-1286; Amin, K., etal., Am. J. Resp. Crit. Care Med. 2000, 162(6), 2295-2301; Gauvreau, G.M., et al., Am. J. Resp. Crit. Care Med. 2000, 161(5), 1473-1478;Kassel, O., et al., Clin. Exp. Allergy 2001, 31(9), 1432-1440). Inaddition, it is known that in response to allergens there is aredistribution of mast cells to the epithelial lining of the nasalmucosa (Fokkens, W. J., et al., Clin. Exp. Allergy 1992, 22(7), 701-710;Slater, A., et al., J. Laryngol. Otol. 1996, 110, 929-933). Theseresults show that the chemotactic response of mast cells to histamine ismediated by histamine H₄ receptors.

It has been shown that eosinophils can chemotax towards histamine(O'Reilly, M., et al., J. Recept. Signal Transduction 2002, 22(1-4),431-448; Buckland, K. F., et al., Br. J. Pharmacol. 2003, 140(6),1117-1127; Ling et al., 2004). Using H₄ selective ligands, it has beenshown that histamine-induced chemotaxis of eosinophils is mediatedthrough the H₄ receptor (Buckland, et al., 2003; Ling et al., 2004).Cell surface expression of adhesion molecules CD11b/CD18 (LFA-1) andCD54 (ICAM-1) on eosinophils increases after histamine treatment (Ling,et al., 2004). This increase is blocked by H₄ receptor antagonists butnot by H₁, H₂, or H₃ receptor antagonists.

The H₄R also plays a role in dendritic cells and T cells. In humanmonocyte-derived dendritic cells, H₄R stimulation suppresses IL-12p70production and drives histamine-mediated chemotaxis (Gutzmer, R., etal., J. Immunol. 2005, 174(9), 5224-5232). A role for the H₄ receptor inCD8⁺T cells has also been reported. Gantner, et al., (2002) showed thatboth H₄ and H₂ receptors control histamine-induced IL-16 release fromhuman CD8+ T cells. IL-16 is found in the bronchoalveolar fluid ofallergen- or histamine-challenged asthmatics (Mashikian, V. M., et al.,J. Allergy Clin. Immunol. 1998, 101 (6, Part 1), 786-792; Krug, N., etal., Am. J. Resp. Crit. Care Med. 2000, 162(1), 105-111) and isconsidered important in CD4⁺ cell migration. The activity of thereceptor in these cell types indicates an important role in adaptiveimmune responses such as those active in autoimmune diseases.

In vivo H₄ receptor antagonists were able to block neutrophillia inzymosan-induced peritonitis or pleurisy models (Takeshita, K., et al.,J. Pharmacol. Exp. Ther. 2003, 307(3), 1072-1078; Thurmond, et al.,2004). In addition, H₄ receptor antagonists have activity in a widelyused and well-characterized model of colitis (Varga, C., et al., Eur. J.Pharmacol. 2005, 522(1-3), 130-138). These results support theconclusion that H₄ receptor antagonists have the capacity to beanti-inflammatory in vivo.

Another physiological role of histamine is as a mediator of itch and H₁receptor antagonists are not completely effective in the clinic.Recently, the H₄ receptor has also been implicated in histamine-inducedscratching in mice (Bell, J. K., et al., Br. J. Pharmacol. 2004, 142(2),374-380). The effects of histamine could be blocked by H₄ antagonists.These results support the hypothesis that the H₄ receptor is involved inhistamine-induced itch and that H₄ receptor antagonists will thereforehave positive effects in treating pruritis. Histamine H₄ receptorantagonists have been shown to attenuate experimental pruritis (Dunford,P. J. et al. J. Allergy Clin. Immunol. 2007, 119(1), 176-183).

Modulation of H₄ receptors controls the release of inflammatorymediators and inhibits leukocyte recruitment, thus providing the abilityto prevent and/or treat H₄-mediated diseases and conditions, includingthe deleterious effects of allergic responses such as inflammation.Compounds according to the present invention have H₄ receptor modulatingproperties. Compounds according to the present invention have leukocyterecruitment inhibiting properties. Compounds according to the presentinvention have anti-inflammatory properties.

Examples of textbooks on the subject of inflammation include: 1) Gallin,J. I.; Snyderman, R., Inflammation: Basic Principles and ClinicalCorrelates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999;2) Stvrtinova, V., et al., Inflammation and Fever. PathophysiologyPrinciples of Diseases (Textbook for Medical Students); Academic Press:New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B.Saunders Co., 1988; and 4) Stedman's Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following:Nathan, C., Nature 2002, 420(6917), 846-852; Tracey, K. J., Nature 2002,420(6917), 853-859; Coussens, L. M., et al., Nature 2002, 420(6917),860-867; Libby, P., Nature 2002, 420, 868-874; Benoist, C., et al.,Nature 2002, 420(6917), 875-878; Weiner, H. L., et al., Nature 2002,420(6917), 879-884; Cohen, J., Nature 2002, 420(6917), 885-891;Steinberg, D., Nature Med. 2002, 8(11), 1211-1217.

Thus, small-molecule histamine H₄ receptor modulators according to thisinvention control the release of inflammatory mediators and inhibitleukocyte recruitment, and may be useful in treating inflammation ofvarious etiologies, including the following conditions and diseases:inflammatory disorders, allergic disorders, dermatological disorders,autoimmune disease, lymphatic disorders, pruritis, and immunodeficiencydisorders. Diseases, disorders and medical conditions that are mediatedby histamine H₄ receptor activity include those referred to herein.

Certain cyclic amine-substituted 2-aminopyrimidines are disclosed in thefollowing publications: Becker, I. J. Het. Chem. 2005, 42(7), 1289-1295;Eur. Pat. Appl. No. EP 1437348 (Jul. 14, 2004); U.S. Pat. No. 3,907,801(Sep. 23, 1975); Lespagnol, A. et al. Chim. Therap. 1971, 6(2), 105-108;Willecomme, B. Annales de Chimie 1969, 4(6), 405-428; Lespagnol, A. etal. Chim. Therap. 1965, 1, 26-31; Intl. Pat. Appl. Publ. WO 2001/62233(Aug. 30, 2007); and Intl. Pat. Appl. Publ. WO 2001/47921 (Jul. 5,2001).

Certain substituted 2-aminopyrimidines as histamine H₄ antagonists aredisclosed in Intl. Pat. Appl. Publ. WO2005/054239 (Jun. 16, 2005) and EP1505064 (Feb. 9, 2005; equivalent of Intl. Pat. Appl. Publ.WO2005/014556). Substituted pyrimidines are described as histamine H₄ligands in U.S. Pat. Appl. Publ. 2007/0185075 (Aug. 9, 2007) and Intl.Pat. Appl. Publ. WO2007/031529 (Mar. 22, 2007). Benzofuro- andbenzothienopyrimidines are disclosed as histamine H₄ modulators in Intl.Pat. Appl. Publ. WO2008/008359 (Jan. 17, 2008). Additional disclosuresof amino pyrimidines as histamine H₄ ligands include: Intl. Pat. Appl.Publ. Nos. WO2007/090852, WO2007/090853, and WO2007/090854 (Aug. 16,2007), and EP 1767537 (Mar. 28, 2007).

However, there remains a need for potent histamine H₄ receptormodulators with desirable pharmaceutical properties. Certain2-aminopyrimidine derivatives have been found in the context of thisinvention to have histamine H₄ receptor-modulating activity.

SUMMARY OF THE INVENTION

In one aspect the invention relates to chemical entity selected fromcompounds of the following Formula (I):

wherein

-   R¹ is:    -   a) a C₁₋₆alkyl group, optionally substituted with —OH,        —OC₁₋₄alkyl, —CF₃, or —O-(monocyclic cycloalkyl);    -   b) a benzyl, —CH₂-(monocyclic heteroaryl), or phenethyl group,        each optionally substituted with halo;    -   c) a monocyclic cycloalkyl, —(CH₂)₀₋₁-tetrahydrofuranyl, or        —(CH₂)₀₋₁-tetrahydropyranyl group, each optionally fused to a        phenyl ring, and each optionally substituted with C₁₋₄alkyl or        phenyl; or    -   d) an adamantyl group;-   R² is H, F, methyl, or methoxy;-   or R¹ and R² taken together form —(CH₂)₃₋₅— or —(CH₂)₂OCH₂—; and-   —N(R³)R⁴ is one of the following acyclic, monocyclic, spirocyclic,    bridged, or fused ring systems:

-   -   where q is 0 or 1;    -   R³ and R⁴ are taken together as defined by the structure of each        one of such moieties;    -   R^(a) is H or OH;    -   R^(b) and R^(c) are each independently H or C₁₋₃alkyl; and    -   each R^(d) substituent is methyl or two R^(d) substituents taken        together form a methylene or ethylene bridge;

-   provided that when R¹ is methyl, then —N(R³)R⁴ is selected from said    spirocyclic, bridged, and fused ring systems;

-   and pharmaceutically acceptable salts of compounds of Formula (I),

-   pharmaceutically acceptable prodrugs of compounds of Formula (I),    and

-   pharmaceutically active metabolites of Formula (I).

In certain embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onechemical entity selected from compounds of Formula (I), pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of Formula (I). Pharmaceutical compositions accordingto the invention may further comprise a pharmaceutically acceptableexcipient.

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by histamine H₄ receptor activity, comprisingadministering to the subject in need of such treatment an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is inflammation. Inflammation hereinrefers to the response that develops as a consequence of histaminerelease, which in turn is caused by at least one stimulus. Examples ofsuch stimuli are immunological stimuli and non-immunological stimuli.

In another aspect, the chemical entities of the present invention areuseful as histamine H₄ receptor modulators. Thus, the invention isdirected to a method for modulating histamine H₄ receptor activity,including when such receptor is in a subject, comprising exposinghistamine H₄ receptor to an effective amount of at least one chemicalentity selected from compounds of Formula (I), pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of compounds of Formula (I).

In another aspect, the present invention is directed to methods ofmaking compounds of Formula (I) and pharmaceutically acceptable saltsthereof.

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS

For the sake of brevity, the disclosures of the publications, includingpatents, cited in this specification are herein incorporated byreference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by a bond,“/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, and heterocycloalkyl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to representhydrates, solvates, and polymorphs of such compounds, and mixturesthereof. In certain embodiments of the invention, pharmaceuticallyacceptable salts of compounds of Formula (I) were obtained in acrystalline form. In a preferred embodiment, bis hydrochloride salts ofcompounds of Formula (I) were obtained in a crystalline form.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH″ refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In this regard, if such entity is forexample in an aqueous environment, it is understood that the compoundR—COOH is in such same medium, and therefore the entity is being exposedto species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where thesubscript “(aq)” stands for “aqueous” according to its conventionalmeaning in chemistry and biochemistry. A carboxylic acid functionalgroup has been chosen in these nomenclature examples; this choice is notintended, however, as a limitation but it is merely an illustration. Itis understood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopically labelled compoundsare useful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(a-d), and q, and any other generic substituent symbol usedherein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(a-d), and q, and any other generic substituent symbol usedherein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

In some embodiments of Formula (I), R¹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, methoxymethyl, ethoxymethyl,isopropoxymethyl, tert-butoxymethyl, 3,3,3-trifluoropropyl,cyclopropoxymethyl, benzyl, 4-chlorobenzyl, thiophen-2-ylmethyl,thiophen-3-ylmethyl, pyridin-4-ylmethyl, phenethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-phenyl-cyclopropyl, indan-2-yl,tetrahydrofuran-3-yl, tetrahydropyran-4-yl,4-methyl-tetrahydro-pyran-4-yl, 2,3-dihydro-benzofuran-2-yl,tetrahydrofuran-2-ylmethyl, or adamantyl. In other embodiments, R¹ iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, R² is H.

In some embodiments, R¹ and R² taken together form —(CH₂)₄—. In otherembodiments, R¹ and R² taken together form —(CH₂)₂OCH₂—.

In some embodiments, —N(R³)R⁴ is:

where R^(a), R^(b), and R^(c) are as previously defined. In furtherembodiments, —N(R³)R⁴ is:

where R^(b) is as previously defined. In still further embodiments,—N(R³)R⁴ is:

In still further embodiments, —N(R³)R⁴ is:

where R^(b) and R^(c) are as previously defined. In still furtherembodiments, —N(R³)R⁴ is:

where R^(b) is as previously defined. In still further embodiments,—N(R³)R⁴ is:

where R^(b) is as previously defined. In still further embodiments,—N(R³)R⁴ is:

where R^(b) is as previously defined.

In some embodiments, R^(a) is H.

In some embodiments, R^(b) and R^(c) are each independently H or methyl.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove and of the specific compounds exemplified herein, and methodsusing such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

Where the compound of Formula (I) contains a plurality of basicnitrogens, one skilled in the art will recognize that suitable saltsinclude salts formed with one or more equivalents of an inorganic ororganic acid. In preferred embodiments of Formula (I), such saltsinclude bis hydrochloride salts.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as benzylamines, pyrrolidines, piperidine,morpholine, and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.

Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I), and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997,40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites, whether alone or in combination, (collectively, “activeagents”) of the present invention are useful as histamine H₄ receptormodulators in the methods of the invention. Such methods for modulatinghistamine H₄ receptor activity comprise exposing histamine H₄ receptorto an effective amount of at least one chemical entity selected fromcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I), and pharmaceutically active metabolites of compounds ofFormula (I). Embodiments of this invention inhibit histamine H₄ receptoractivity.

In some embodiments, the histamine H₄ receptor is in a subject diagnosedwith or suffering from a disease, disorder, or medical conditionmediated through histamine H₄ receptor activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “medical conditions, disorders, or diseases.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated through histamine H₄ receptoractivity, such as inflammation. Active agents according to the inventionmay therefore be used as anti-inflammatory agents.

In some embodiments, an active agent of the present invention isadministered to treat inflammation. Inflammation may be associated withvarious diseases, disorders, or conditions, such as inflammatorydisorders, allergic disorders, dermatological disorders, autoimmunedisease, lymphatic disorders, and immunodeficiency disorders, includingthe more specific conditions and diseases given below. Regarding theonset and evolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Illustrative types of inflammation treatable with a histamine H₄receptor-modulating agent according to the invention includeinflammation due to any one of a plurality of conditions such asallergy, asthma, dry eye, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis (see: Ohki, E. et al. Biol. Pharm.Bull. 2007, 30(11), 2217-2220), multiple sclerosis, inflammatory boweldiseases (including colitis, Crohn's disease, and ulcerative colitis),psoriasis, pruritis, itchy skin, atopic dermatitis, urticaria (hives),ocular inflammation (e.g., post-surgical ocular inflammation),conjunctivitis, dry eye, nasal polyps, allergic rhinitis, nasal itch,scleroderma, autoimmune thyroid diseases, immune-mediated (also known astype 1) diabetes mellitus and lupus, which are characterized byexcessive or prolonged inflammation at some stage of the disease. Otherautoimmune diseases that lead to inflammation include Myasthenia gravis,autoimmune neuropathies, such as Guillain-Barré, autoimmune uveitis,autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides, such as Wegener's granulomatosis, Behcet's disease,dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliarycirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland, polymyositis, dermatomyositis,spondyloarthropathies, such as ankylosing spondylitis, and Sjogren'ssyndrome.

Pruritis treatable with a histamine H₄ receptor-modulating agentaccording to the invention includes that which is a symptom of allergiccutaneous diseases (such as atopic dermatitis and hives) and othermetabolic disorders (such as chronic renal failure, hepatic cholestasis,and diabetes mellitus).

In other embodiments, an active agent of the present invention isadministered to treat allergy, rheumatoid arthritis, asthma, autoimmunediseases, or pruritis.

Thus, the active agents may be used to treat subjects diagnosed with orsuffering from a disease, disorder, or condition mediated throughhistamine H₄ receptor activity. The term “treat” or “treating” as usedherein is intended to refer to administration of an active agent orcomposition of the invention to a subject for the purpose of effecting atherapeutic or prophylactic benefit through modulation of histamine H₄receptor activity. Treating includes reversing, ameliorating,alleviating, inhibiting the progress of, lessening the severity of, orpreventing a disease, disorder, or condition, or one or more symptoms ofsuch disease, disorder or condition mediated through modulation ofhistamine H₄ receptor activity. The term “subject” refers to a mammalianpatient in need of such treatment, such as a human. “Modulators” includeboth inhibitors and activators, where “inhibitors” refer to compoundsthat decrease, prevent, inactivate, desensitize or down-regulatehistamine H₄ receptor expression or activity, and “activators” arecompounds that increase, activate, facilitate, sensitize, or up-regulatehistamine H₄ receptor expression or activity.

In treatment methods according to the invention, an effective amount ofat least one active agent according to the invention is administered toa subject suffering from or diagnosed as having such a disease,disorder, or condition. An “effective amount” means an amount or dosesufficient to generally bring about the desired therapeutic orprophylactic benefit in patients in need of such treatment for thedesignated disease, disorder, or condition. Effective amounts or dosesof the active agents of the present invention may be ascertained byroutine methods such as modeling, dose escalation studies or clinicaltrials, and by taking into consideration routine factors, e.g., the modeor route of administration or drug delivery, the pharmacokinetics of theagent, the severity and course of the disease, disorder, or condition,the subject's previous or ongoing therapy, the subject's health statusand response to drugs, and the judgment of the treating physician. Anexemplary dose is in the range of from about 0.001 to about 200 mg ofactive agent per kg of subject's body weight per day, preferably about0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, or about 0.1 to 10mg/kg daily in single or divided dosage units (e.g., BID, TID, QID). Fora 70-kg human, an illustrative range for a suitable dosage amount isfrom about 1 to 200 mg/day, or about 5 to 50 mg/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of Formula (I) orincluded with such an agent in a pharmaceutical composition according tothe invention. In an exemplary embodiment, additional active ingredientsare those that are known or discovered to be effective in the treatmentof conditions, disorders, or diseases mediated by histamine H₄ receptoractivity, such as another histamine H₄ receptor modulator or a compoundactive against another target associated with the particular condition,disorder, or disease. The combination may serve to increase efficacy(e.g., by including in the combination a compound potentiating thepotency or effectiveness of an agent according to the invention),decrease one or more side effects, or decrease the required dose of theactive agent according to the invention.

When referring to modulating the target receptor, an “effective amount”means an amount sufficient to affect the activity of such receptor.Measuring the activity of the target receptor may be performed byroutine analytical methods. Target receptor modulation is useful in avariety of settings, including assays.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., from about 0.05 to about 50mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Each of the reactions depicted in Scheme A ispreferably run at a temperature from about room temperature to thereflux temperature of the organic solvent used. Unless otherwisespecified, the variables are as defined above in reference to Formula(I).

As shown in Scheme A, the present invention includes methods of makingcompounds of Formula (I), from β-ketoesters A1 (where R is C₁₋₄alkyl;preferably methyl or ethyl), which are commercially available orprepared by known methods. β-Ketoesters A1 are reacted with guanidine,or a hydrochloride, carbonate, nitrate, or sulfate salt thereof, in thepresence of an organic base (for example, potassium tert-butoxide or atertiary amine base, such as triethylamine or diisopropylethylamine) oran inorganic base (for example, K₂CO₃, Na₂CO₃, Cs₂CO₃, or K₃PO₄, or amixture thereof), in an organic solvent (for example, methanol, ethanol,isopropanol, tert-amyl alcohol, THF, acetonitrile, or methyl tert-butylether (MTBE), or a mixture thereof), to provide hydroxypyrimidines A2.One skilled in the art will recognize that compounds of formula A2include hydroxypyrimidines and their pyrimidone tautomers, and mixturesthereof.

Chlorination of compounds A2 with POCl₃, neat or in an organic solvent(for example, acetonitrile, toluene, dichloromethane, or MTBE, or amixture thereof), provides chloro-pyrimidines A3. In preferredembodiments, the reaction is done in the presence of a tertiary aminebase (for example, dimethylaniline, diethylaniline, or iPr₂NEt) and atetraalkylammonium chloride salt (such as Et₄NCl).

Displacement of the chloro substituent by reacting a chloro-pyrimidineA3 with a diamine HNR³R⁴, in an organic solvent (for example, methanol,ethanol, isopropanol, tert-amyl alcohol, THF, or acetonitrile, or amixture thereof), gives compounds of Formula (I). In some embodiments ofthe displacement reaction, the R^(b) substituent in diamine HNR³R⁴ is anitrogen protecting group, such as a tert-butoxycarbonyl (Boc) group orbenzyl group, and the reaction provides compounds of formula (Ia) whereR^(b) is a nitrogen protecting group.

Where the R^(b) group in diamine HNR³R⁴ is a nitrogen protecting group,the protecting group is removed by deprotecting compounds of formula(Ia) to give compounds of Formula (I) where R^(b) is H. Deprotection maybe accomplished using standard deprotection conditions. For example, atert-butoxycarbonyl group is removed using an organic acid such as TFA(neat or in a solvent such as CH₂Cl₂) or an inorganic acid such as HCl(in a solvent such as 1,4-dioxane, isopropanol, or formic acid) to givea compound of Formula (I) where R^(b) is H.

In an alternative embodiment, reaction of hydroxypyrimidines A2 withprotected or unprotected diamines HNR³R⁴ under standard peptide couplingconditions known in the art provide compounds of Formula (I) directly.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods described in the art. For example, an amine of Formula (I)is treated with trifluoroacetic acid, HCl, or citric acid in a solventsuch as Et₂O, CH₂Cl₂, THF, MeOH, or isopropanol to provide thecorresponding salt form. Cyrstalline forms of pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained incrystalline form by recrystallization from polar solvents (includingmixtures of polar solvents and aqueous mixtures of polar solvents) orfrom non-polar solvents (including mixtures of non-polar solvents).

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions are “dried,” they are generallydried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures,solutions, and extracts were “concentrated”, they were typicallyconcentrated on a rotary evaporator under reduced pressure. Silica gel(SiO₂) was used for all chromatographic purification unless otherwisenoted and the eluent used is listed in parentheses.

Analytical reversed-phase HPLC was performed on a Hewlett Packard HPLCSeries 1100, with a Phenomenex ONYX® monolithic C18 (5 μm, 4.6×100 mm)column. Detection was done at λ=230, 254 and 280 nm. The flow rate was 1mL/min. The gradient was 10 to 90% acetonitrile/water (20 mM NH₄OH) over5.0 min. Preparative reversed-phase HPLC was performed on a ShimadzuLC-8A equipped with a YMC Pack ODS 250×30 mm column with a gradient of10 to 50% TFA in acetonitrile (0.05% water) over 15 min at a flow rateof 70 mL/min.

Compounds were analyzed in a free base, hydrochloride salt, ortrifluoroacetic acid salt form. Hydrochloride salts were obtainedeither: 1) during the removal of the tert-butylcarbamoyl (Boc) group; or2) by treatment of a solution of the purified free base in THF or CH₂Cl₂with at least two equivalents of a solution of HCl in 1,4-dioxanefollowed by concentration. TFA salts were obtained following preparativereversed-phase HPLC purification.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. The MS data presented is the m/z found (typically [M+H]⁺) forthe molecular ion.

Chemical names were generated using Chem Draw Version 6.0.2(CambridgeSoft, Cambridge, Mass.) or ACD/Name Version 9 (AdvancedChemistry Development, Toronto, Ontario, Canada).

Example 1 4-Cyclopentyl-6-piperazin-1-yl-pyrimidin-2-ylamine

Step A: 2-Amino-6-cyclopentyl-3H-pyrimidin-4-one. To a solution of3-cyclopentyl-3-oxo-propionic acid ethyl ester (5.0 g, 27.4 mmol) andguanidine hydrochloride (3.1 g, 33.0 mmol) in MeOH (50 mL) at 23° C. wasadded potassium tert-butoxide, portionwise (16.7 g. 149 mmol) over 15min with vigorous stirring and the reaction warmed to 60° C. Thereaction was cooled to room temperature (rt) and stirred overnight andthe precipitated salt was removed by filtration. The solution wasconcentrated to approximately 10 mL then diluted with 10 mL of water andadjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL). The resultingprecipitate was filtered and dried via suction then vacuum to yield awhite solid (4.3 g, 87%) that was used without further purification. ¹HNMR (MeOD): 10.71-10.54 (m, 1H), 6.58-6.32 (m, 2H), 5.44-5.37 (m, 1H),2.66 (p, J=8.1, 1H), 1.91-1.73 (m, 2H), 1.72-1.48 (m, 6H).

Step B: 2-Amino-4-chloro-6-cyclopentylpyrimidine. A suspension of2-amino-6-cyclopentyl-3H-pyrimidin-4-one (1.52 g, 8.4 mmol), tetraethylammonium chloride (2.8 g 16.9 mmol) and dimethylaniline (1.1 mL, 8.4mmol) in acetonitrile (16 mL) was treated with phosphorous oxychloride(4.7 mL, 51 mmol) and heated at 110° C. for 20 min. The resultingsolution was cooled to rt and concentrated to minimum volume thendiluted with CHCl₃ and ice and stirred for 30 min. The layers wereseparated and the organic layer was washed with water (3×50 mL) and 5%NaHCO₃, dried, and concentrated to yield 2.0 g of crude product that wasused without purification.

Step C: 4-Cyclopentyl-6-piperazin-1-yl-pyrimidin-2-ylamine. A solutionof crude 2-amino-4-chloro-6-cyclopentylpyrimidine (150 mg, 0.76 mmol),N-BOC piperazine (184 mg, 0.99 mmol) and Et₃N (210 uL, 1.5 mmol) in EtOH(2 mL) was heated at 70° C. for 16 h. The reaction was cooled to rt andconcentrated and the crude residue purified (2 M NH₃ in MeOH/CH₂Cl₂) toyield a white solid (34 mg, 11%). MS (ESI): mass calcd. for C₁₈H₂₉N₅O₂,347.2; m/z found, 348.3 [M+H]⁺. ¹H NMR (MeOD): 6.01 (s, 1H), 3.66-3.58(m, 4H), 3.53-3.43 (m, 4H), 3.33 (td, J=3.3, 1.6, 1H), 2.90-2.75 (m,1H), 2.05-1.90 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.62 (m, 4H), 1.53-1.46(m, 9H).

Step D: 4-Cyclopentyl-6-piperazin-1-yl-pyrimidin-2-ylamine. A solutionof 4-cyclopentyl-6-piperazin-1-yl-pyrimidin-2-ylamine (34 mg, 0.10 mmol)in formic acid (3 mL) was treated with 6.0 N HCl (0.1 mL) and stirredfor 2 h. The reaction was diluted with MeOH and concentrated. Thisprocess was repeated twice to remove the formic acid to yield a whitesolid (30 mg, 97%). MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/zfound, 248.2 [M+H]⁺. ¹H NMR (MeOD): 6.45 (s, 1H), 4.34-4.16 (m, 2H),4.13-3.96 (m, 2H), 3.42-3.34 (m, 4H), 3.03 (p, J=8.0, 1H), 2.22-2.08 (m,2H), 1.99-1.83 (m, 2H), 1.83-1.65 (m, 4H).

Example 2 4-Cyclopentyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

A solution of crude 2-amino-4-chloro-6-cyclopentylpyrimidine (92 mg,0.47 mmol), and N-methyl piperazine (0.15 mL, 1.4 mmol) in EtOH (2 mL)was heated at 70° C. for 2 h. The reaction was cooled to rt andconcentrated and the crude residue chromatographed (2 M NH₃ inMeOH/CH₂Cl₂) to yield an oil (81 mg, 66%). MS (ESI): mass calcd. forC₁₄H₂₃N₅, 261.2; m/z found, 262.3 [M+H]⁺. ¹H NMR (CDCl₃): 5.85 (s, 1H),4.78 (s, 2H), 3.59 (t, J=5.0, 4H), 2.81 (q, J=8.7, 1H), 2.44 (t, J=5.0,4H), 2.32 (s, 3H), 2.04-1.89 (m, 2H), 1.82-1.59 (m, 6H).

The compounds in Examples 3-36 were prepared using methods analogous tothose described for Examples 1 and 2. Where amines used in Example 1,Step C or Example 2 were not protected, the deprotection step describedin Example 1, Step D was omitted.

Example 3(R)-4-(3-Amino-piperidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2; m/z found, 262.2 [M+H]⁺.

Example 4(R)-4-Cyclopentyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.4; m/z found, 262.3 [M+H]⁺. ¹HNMR (MeOD): 5.75 (s, 1H), 3.74-3.51 (m, 2H), 3.52-3.39 (m, 1H),3.37-3.30 (m, 2H), 2.86-2.75 (m, 1H), 2.41 (s, 3H), 2.27-2.14 (m, 1H),2.05-1.92 (m, 2H), 1.93-1.83 (m, 1H), 1.84-1.73 (m, 2H), 1.73-1.60 (m,4H).

Example 5trans-1-(2-Amino-6-cyclopentyl-pyrimidin-4-yl)-4-methylamino-pyrrolidin-3-ol

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, 278.1 [M+H]⁺. ¹HNMR (CDCl₃): 5.52 (s, 1H), 5.34-5.17 (m, 2H), 4.17-4.07 (m, 1H),3.75-3.56 (m, 2H), 3.40-3.08 (m, 4H), 3.10-3.02 (m, 1H), 2.78-2.66 (m,1H), 2.37 (s, 3H), 1.96-1.84 (m, 2H), 1.75-1.63 (m, 2H), 1.63-1.49 (m,4H).

Example 64-Cyclopentyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.2; m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.63 (s, 1H), 5.36-5.13 (m, 2H), 3.97-3.85 (m, 1H),3.78-3.63 (m, 1H), 3.64-3.54 (m, 1H), 3.56-3.42 (m, 1H), 3.38-3.22 (m,1H), 3.20-3.04 (m, 2H), 3.05-2.92 (m, 2H), 2.92-2.75 (m, 2H), 2.11-1.89(m, 3H), 1.86-1.57 (m, 7H).

Example 74-Cyclopentyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.2; m/z found, 288.2 [M+H]⁺. ¹HNMR (MeOD): 6.13 (s, 1H), 4.13-4.04 (m, 1H), 4.02-3.79 (m, 3H),3.71-3.58 (m, 1H), 3.42-3.34 (m, 1H), 3.17-2.79 (m, 3H), 2.22-2.09 (m,2H), 2.03-1.68 (m, 10H).

Example 8 4-Isopropyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.2; m/z found, 222.1 [M+H]⁺. ¹HNMR (MeOD): 5.99 (s, 1H), 3.66-3.62 (m, 4H), 2.93-2.84 (m, 4H), 2.67 (q,J=7.0, 1H), 1.21 (d, J=7.0, 6H).

Example 9 (R)-4-(3-Amino-piperidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.2; m/z found, 236.2 [M+H]⁺.

Example 10(S)-4-(3-Amino-piperidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.2; m/z found, 236.2 [M+H]⁺.

Example 11(R)-4-Isopropyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.2; m/z found, 236.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.66 (s, 1H), 5.00-4.87 (m, 2H), 3.75-3.56 (m, 2H),3.56-3.43 (m, 1H), 3.43-3.23 (m, 2H), 2.71 (q, J=6.9, 1H), 2.53 (s, 3H),2.22 (dt, J=13.4, 6.1, 1H), 1.98-1.81 (m, 1H), 1.26 (d, J=6.9, 6H).

Example 12(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.16; m/z found, 222.2 [M+H]⁺. ¹HNMR (MeOD; mixture of forms): 6.10 (s, 0.67H), 6.08 (s, 0.33H),4.16-3.68 (m, 5H), 2.89 (sept, J=6.9, 1H), 2.60-2.50 (m, 0.67H),2.50-2.42 (m, 0.33H), 2.32-2.22 (m, 0.67H), 2.22-2.14 (m, 0.33H), 1.33(d, J=7.0, 6H).

Example 13trans-1-(2-Amino-6-isopropyl-pyrimidin-4-yl)-4-methylamino-pyrrolidin-3-ol

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2 m/z found, 252.2 [M+H]⁺.

Example 14(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺.

Example 15(R,R)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺.

Example 164-(cis-Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/z found, 248.2 [M+H]⁺.

Example 17(R,R)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/z found, 248.2 [M+H]⁺.

Example 184-Isopropyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2; m/z found, 262.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.54 (s, 1H), 4.61 (s, 2H), 3.54 (dd, J=10.7, 8.2, 2H),3.30 (d, J=10.3, 2H), 2.91-2.80 (m, 2H), 2.65-2.51 (m, 2H), 2.36 (dd,J=9.5, 3.6, 2H), 2.24 (s, 3H), 1.12 (d, J=6.9, 6H).

Example 194-Isopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2; m/z found, 262.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.45 (s, 1H), 5.42-5.19 (m, 2H), 3.57-3.06 (m, 4H),2.91-2.80 (m, 1H), 2.64-2.46 (m, 3H), 2.29-2.08 (m, 1H), 1.94-1.85 (m,1H), 1.66-1.53 (m, 2H), 1.53-1.43 (m, 1H), 1.40-1.31 (m, 1H), 1.08 (d,J=6.9, 6H).

Example 20(R,R)-4-Isopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2; m/z found, 262.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.45 (s, 1H), 5.42-5.19 (m, 2H), 3.57-3.06 (m, 4H),2.91-2.80 (m, 1H), 2.64-2.46 (m, 3H), 2.29-2.08 (m, 1H), 1.94-1.85 (m,1H), 1.66-1.53 (m, 2H), 1.53-1.43 (m, 1H), 1.40-1.31 (m, 1H), 1.08 (d,J=6.9, 6H).

Example 21 4-Methyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₉H₁₅N₅, 193.2; m/z found, 194.2 [M+H]⁺. ¹HNMR (MeOD): 10.02-9.24 (br. s, 2H), 8.12-7.21 (br.s, 2H), 6.50 (s, 1H),4.14-3.85 (m, 4H), 3.19 (t, J=5.0, 4H).

Example 22 4-Methyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.3; m/z found, 208.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.63 (s, 1H), 4.48 (s, 2H), 3.39 (t, J=5.1, 4H), 2.23 (t,J=5.1, 4H), 2.12 (s, 3H), 2.01 (s, 3H).

Example 23(R)-4-Methyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.2; m/z found, 208.2 [M+H]⁺.

Example 244-Methyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₆N₅, 233.2; m/z found, 234.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 10.00-9.76 (m, 1H), 9.14-8.93 (m, 1H), 7.90-7.42 (m, 1H),6.17 (s, 0.3H), 6.13 (s, 0.7H), 3.96-3.87 (m, 1H), 3.87-3.61 (m, 3H),3.58-3.49 (m, 2H), 3.22-3.11 (m, 1H), 2.94-2.62 (m, 2H), 2.32-2.23 (m,3H), 1.88-1.62 (m, 4H).

Example 25 4,5-Dimethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.1; m/z found, 208.2 [M+H]⁺.

Example 26 4,5-Dimethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₆N₅, 221.2; m/z found, 222.2 [M+H]⁺.

Example 27(R)-4-(3-Amino-pyrrolidin-1-yl)-5,6-dimethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.1; m/z found, 208.2 [M+H]⁺.

Example 28(R)-4,5-Dimethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.2; m/z found, 222.2 [M+H]⁺.

Example 294-(cis-Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-5,6-dimethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺.

Example 304,5-Dimethyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2 m/z found, 248.2 [M+H]⁺.

Example 314,5-Dimethyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/z found, 248.2 [M+H]⁺.

Example 32(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-5,6-dimethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.2; m/z found, 220.2 [M+H]⁺.

Example 33 4-Ethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 207.15; m/z found, 208.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 13.51 (s, 1H), 9.68 (s, 2H), 7.76 (s, 2H), 6.53-6.42 (m,4H), 3.99 (s, 4H), 3.19 (s, 4H), 2.61-2.53 (m, 2H), 1.28-1.19 (m, 3H).

Example 34 4-Ethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁N₁₉N₅, 221.16; m/z found, 222.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.8 (s, 1H), 5.1 (s, 2H), 3.7-3.5 (m, 5H), 2.5-2.4 (m, 6H),2.3 (s, 3H), 1.2 (t, J=7.6, 3H).

Example 35 (R)-4-(3-Amino-pyrrolidin-1-yl)-6-ethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.15; m/z found, 208.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 8.85-8.58 (m, 2H), 8.32-7.18 (m, 1H), 6.17-6.10 (m, 1H),4.04-3.85 (m, 1H), 3.85-3.53 (m, 4H), 2.66-2.53 (q, J=7.5, 2H),2.41-2.09 (m, 2H), 1.28-1.19 (t, J=7.5, 3H)

Example 36(R)-4-Ethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₀N₅, 221.16; m/z found, 222.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.61 (s, 1H), 5.21 (s, 2H), 3.72-3.12 (m, 5H), 2.55-2.41(m, 5H), 2.22-2.09 (m, 1H), 1.93-1.77 (m, 1H), 1.27-1.15 (t, J=7.3, 3H)

Example 37(R,R)-(4-Ethyl-6-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine

Step A:(R,R)-4-Ethyl-6-[1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-pyrimidin-2-ylamine.To a solution of 4-chloro-6-ethyl-pyrimidin-2-ylamine (200 mg, 1.27mmol) in EtOH (2.4 mL) was added pyridine (210 μL, 2.54 mmol) and1-(1-phenyl-ethyl)-octahydro-pyrrolo[3,4-b]pyrrole (360 mg, 1.65 mmol).The solution was stirred for 2 h at 90° C. The compound was purifieddirectly with reversed-phase HPLC to yield 115 mg (28%) of the desiredcompound as a yellow oil.

Step B:(R,R)-(4-Ethyl-6-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine.To a solution of4-ethyl-6-[1-(1-phenyl-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl]-pyrimidin-2-ylamine(110 mg, 0.33 mmol) in EtOH (1.0 mL) at 23° C. was added palladiumhydroxide on carbon (22 mg). The reaction mixture was placed on a Parrhydrogenator and reacted with hydrogen gas at 60 psi for 6 h.

The mixture was filtered through diatomaceous earth, rinsing with EtOAc(3×10 mL). The resulting solution was concentrated and purified withreversed-phase HPLC to yield the desired compound as a colorless oil (65mg, 86%). MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.16; m/z found, 234.2[M+H]⁺. ¹H NMR (CDCl₃): 5.61 (s, 1H), 5.22 (s, 2H), 3.99-3.54 (m, 4H),3.55-3.42 (m, 1H), 3.38-3.23 (m, 1H), 3.16-3.05 (m, 1H), 3.05-2.94 (m,1H), 2.92-2.80 (m, 1H), 2.53-2.42 (q, J=7.1, 2H), 2.08-1.96 (m, 1H),1.83-1.67 (m, 1H), 1.28-1.16 (t, J=7.0, 3H).

The compounds in Examples 38-55 were prepared using methods analogous tothose described in the preceding examples.

Example 384-Ethyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (MeOD): 6.13 (s, 1H), 4.01-3.87 (m, 2H), 3.87-3.78 (m, 1H),3.77-3.58 (m, 1H), 3.45-3.36 (m, 1H), 3.35-3.24 (m, 3H), 2.66 (q, J=7.5,2H), 1.32 (t, J=7.5, 3H).

Example 39(R,R)-(4-Ethyl-6-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.18; m/z found, 248.2 [M+H]⁺. ¹HNMR (MeOD): 6.14 (s, 1H), 4.17-3.79 (m, 4H), 3.77-3.60 (m, 1H),3.45-3.29 (m, 2H), 3.19-3.02 (m, 1H), 3.01-2.80 (m, 1H), 2.77-2.60 (m,2H), 2.09-1.78 (m, 4H), 1.44-1.24 (m, 3H).

Example 40 4-Cyclopropyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₆N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.81 (s, 1H), 4.75 (s, 2H), 3.63-3.54 (t, J=4.9, 4H),2.46-2.40 (t, J=5.0, 4H), 2.32 (s, 3H), 1.75-1.67 (m, 1H), 1.00-0.94 (m,2H), 0.89-0.82 (m, 2H).

Example 41(R)-(4-Cyclopropyl-6-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₆N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.58 (s, 1H), 5.30 (s, 1H), 4.73-4.63 (m, 1H), 3.75-3.11(m, 5H), 2.46 (s, 3H), 2.21-2.10 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.77(m, 1H), 1.77-1.67 (m, 1H), 1.00-0.91 (m, 2H), 0.89-0.82 (m, 2H).

Example 424-Cyclopropyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅, 259.18; m/z found, 260.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.45 (s, 1H), 9.91-9.74 (m, 1H), 8.96-8.83 (m, 1H),8.12-7.21 (m, 2H), 6.06 (s, 0.3H), 6.00 (s, 0.7H), 3.96-3.63 (m, 5H),3.22-3.12 (m, 1H), 2.94-2.82 (m, 1H), 2.80-2.63 (m, 1H), 2.03-1.90 (m,1H), 1.88-1.60 (m, 4H), 1.19-1.04 (m, 4H).

Example 43 4-Cyclobutyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.67 (s, 1H), 9.45 (s, 2H), 8.33-7.25 (m, 1H), 6.43 (s,1H), 4.16-3.88 (m, 4H), 3.28-3.15 (m, 4H), 2.37-2.19 (m, 4H), 2.10-1.95(m, 1H), 1.90-1.78 (m, 1H).

Example 44 4-Cyclobutyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.18; m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.82 (s, 1H), 4.81 (s, 2H), 3.60 (t, J=4.9, 4H), 2.44 (t,J=5.0, 4H), 2.32 (s, 3H), 2.28-2.18 (m, 5H), 2.07-1.93 (m, 1H),1.91-1.78 (m, 1H).

Example 45(R)-4-(3-Amino-piperidin-1-yl)-6-cyclobutyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.18; m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.84 (s, 1H), 4.91 (s, 2H), 4.32-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.49-3.43 (m, 1H), 3.40-3.26 (m, 1H), 3.11-2.64 (m, 4H),2.36-2.15 (m, 4H), 2.12-1.93 (m, 2H), 1.91-1.71 (m, 2H), 1.65-1.48 (m,1H), 1.44-1.22 (m, 1H).

Example 46(R)-4-Cyclobutyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.18; m/z found, 248.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.62 (s, 1H), 4.71 (s, 2H), 3.75-3.52 (m, 2H), 3.50-3.39(m, 1H), 3.38-3.20 (m, 3H), 2.52-2.44 (s, 3H), 2.33-2.10 (m, 5H),2.09-1.76 (m, 5H).

Example 474-Cyclobutyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅, 259.18; m/z found, 260.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.63 (s, 1H), 4.71 (s, 2H), 3.94-3.87 (m, 1H), 3.73-3.63(m, 1H), 3.63-3.56 (m, 1H), 3.53-3.42 (m, 1H), 3.39-3.24 (m, 2H),3.14-3.05 (m, 1H), 3.02-2.94 (m, 1H), 2.90-2.81 (m, 1H), 2.31-2.16 (m,4H), 2.08-1.94 (m, 2.5H), 1.89-1.79 (m, 1.5H), 1.77-1.69 (m, 1H).

Example 484-Cyclobutyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅, 259.18; m/z found, 260.2 [M+H]⁺. ¹HNMR (MeOD): 6.05 (s, 1H), 3.98-3.86 (m, 2H), 3.85-3.78 (m, 1H),3.77-3.69 (m, 1H), 3.69-3.59 (m, 2H), 3.58-3.48 (m, 1H), 3.43-3.23 (m,3H), 2.44-2.26 (m, 4H), 2.21-2.07 (m, 1H), 1.99-1.89 (m, 1H).

Example 494-Cyclobutyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.20; m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.64 (s, 1H), 4.75 (s, 1H), 3.68-3.57 (m, 2H), 3.44-3.27(m, 3H), 2.98-2.90 (m, 2H), 2.73-2.66 (m, 2H), 2.47-2.41 (m, 2H), 2.32(s, 3H), 2.28-2.14 (m, 5H), 2.06-1.94 (m, 2H), 1.89-1.78 (m, 1H),1.48-1.43 (m, 1H).

Example 504-Cyclobutyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.20; m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.61 (s, 1H), 4.85 (s, 2H), 3.69-3.17 (m, 6H), 3.06-2.92(m, 1H), 2.69-2.61 (m, 1H), 2.44-2.12 (m, 5H), 2.08-1.91 (m, 1H),1.89-1.57 (m, 4H), 1.55-1.43 (m, 1H).

Example 51(R,R)-(4-Cyclobutyl-6-cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.20; m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.61 (s, 1H), 4.85 (s, 2H), 3.69-3.17 (m, 6H), 3.06-2.92(m, 1H), 2.69-2.61 (m, 1H), 2.44-2.12 (m, 5H), 2.08-1.91 (m, 1H),1.89-1.57 (m, 4H), 1.55-1.43 (m, 1H).

Example 52 4-Cyclohexyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.80 (s, 1H), 4.71 (s, 2H), 3.59 (t, J=5.1, 4H), 2.44 (t,J=5.1, 4H), 2.32 (s, 3H), 1.93-1.86 (m, 2H), 1.85-1.77 (m, 2H),1.76-1.68 (m, 1H), 1.47-1.18 (m, 6H).

Example 53(R)-(4-Cyclohexyl-6-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.59 (s, 1H), 5.30 (s, 2H), 4.69 (s, 2H), 3.71-3.51 (m,2H), 3.46-3.38 (m, 1H), 3.37-3.29 (m, 1H), 2.47 (s, 3H), 2.36-2.26 (m,1H), 2.22-2.12 (m, 1.5H), 1.95-1.77 (m, 5.5H), 1.76-1.68 (m, 1H),1.47-1.17 (m, 6H).

Example 544-Cyclohexyl-6-(cis-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.21; m/z found, 288.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.59 (s, 1H), 4.89 (s, 2H), 4.02-3.81 (m, 1H), 3.73-3.63(m, 1H), 3.62-3.53 (m, 1H), 3.52-3.47 (m, 1H), 3.35-3.22 (m, 1H),3.21-2.94 (m, 2H), 2.91-2.78 (m, 1H), 2.76-2.40 (m, 2H), 2.38-2.27 (m,1H), 2.12-1.96 (m, 1H), 1.94-1.86 (m, 2H), 1.85-1.77 (m, 2H), 1.76-1.67(m, 2H), 1.48-1.17 (m, 5H).

Example 55(R,R)-4-Cyclohexyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₇N₅, 301.23; m/z found, 302.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.59 (s, 1H), 4.84 (s, 2H), 3.72-3.27 (m, 6H), 3.05-2.94(m, 1H), 2.72-2.60 (m, 1H), 2.47-2.23 (m, 2H), 2.01-1.86 (m, 2H),1.85-1.55 (m, 6H), 1.55-1.19 (m, 6H).

Example 564-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

Step A: 2-Amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one. To asolution of 3-oxo-3-(tetrahydro-furan-3-yl)-propionic acid ethyl ester(4.0 g, 21.5 mmol) and guanidine hydrochloride (2.6 g, 27.2 mmol) inMeOH (125 mL) at 23° C. was added potassium tert-butoxide in portions(3.4 g, 30.3 mmol) over 5 min. The reaction was heated at 80° C. for 18h. The mixture was filtered while warm to remove insoluble salts, andthe filtrate was concentrated to afford an oil which was diluted withwater (˜25 mL) and extracted with EtOAc (8×50 mL). The combined organiclayers were washed with satd. aq. NaCl, dried, and concentrated to givea residue. The aqueous portion was concentrated to afford a solidresidue that was collected and rinsed with MeOH. The residue and solidmaterials were combined and chromatographed (2 M NH₃ in MeOH/EtOAc) toprovide 2.02 g of product as a white solid (51%). MS (ESI): mass calcd.for: C₈H₁₁N₃O₂, 181.1; m/z found, 182.2 [M+H]⁺. ¹H NMR (CD₃OD): 5.66 (brs, 1H), 3.93-4.01 (m, 2H), 3.75-3.85 (m, 2H), 3.28-3.31 (m, 2H),3.16-3.24 (m, 1H), 2.18-2.27 (m, 1H), 2.05-2.15 (m, 1H).

Step B: 4-Chloro-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine. Asuspension of 2-amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one (1.5g, 8.28 mmol), tetraethyl ammonium chloride (2.7 g 16.3 mmol) anddimethylaniline (1.4 mL, 11.1 mmol) in acetonitrile (15 mL) was treatedwith phosphorous oxychloride (2.4 mL, 26.2 mmol) and heated at 110° C.for 20 min. The resulting solution was cooled to rt and concentrated tominimum volume and pipetted onto ice chips. The aqueous portion wasextracted with EtOAc (3×50 mL). The combined organic layers werebasified with satd. aq. NaHCO₃ solution to pH ˜7. The organic portionwas separated, dried, and concentrated. The crude material waschromatographed (MeOH/CH₂Cl₂) to yield 680 mg (42%) of product as alight orange foam. ¹H NMR (CDCl₃): 6.59 (s, 1H), 5.16 (br s, 2H),4.00-4.10 (m, 2H), 3.85-3.91 (m, 2H), 3.28-3.35 (m, 1H), 2.25-2.34 (m,1H), 2.08-2.18 (m, 1H).

Step C:4-[2-Amino-6-(tetrahydro-furan-3-yl)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester. A solution of4-chloro-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine (500 mg, 2.51mmol), N-BOC piperazine (960 mg, 5.15 mmol) and pyridine (500 uL, 6.1mmol) in EtOH (10 mL) was heated at 90° C. for 4 h. Upon cooling to rt athick precipitate formed which was collected by filtration. The materialwas rinsed with EtOAc to afford 125 mg of a white solid. The filtratewas concentrated and triturated with Et₂O-EtOAc (1:1) to yield anadditional 600 mg of material (82% combined). MS (ESI): mass calcd. forC₁₇H₂₇N₅O₃, 349.2; m/z found, 350.3 [M+H]⁺. ¹H NMR (CDCl₃): 5.86 (s,1H), 4.70 (br s, 2H), 3.90-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.55-3.60(m, 4H), 3.45-3.50 (m, 4H), 3.18-3.26 (m, 1H), 2.20-2.30 (m, 1H),2.09-2.18 (m, 1H), 1.48 (s, 9H).

Step D: 4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine.A solution of4-[2-amino-6-(tetrahydro-furan-3-yl)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (600 mg, 1.72 mmol) in formic acid (10 mL) wastreated with 6.0 N HCl (2 mL) and stirred for 2 h at rt. The mixture wasdiluted with MeOH (10 mL) and concentrated. This process was repeatedtwice, yielding 295 mg of a white solid as the hydrochloride salt. Thecrude material was chromatographed (2 M NH₃ in MeOH/CH₂Cl₂) to afford133 mg (50%) of the free base as an off-white solid. MS (ESI): masscalcd. for C₁₂H₁₉N₅O, 249.1; m/z found, 250.2 [M+H]⁺. ¹H NMR (CDCl₃):6.86 (s, 1H), 4.78 (br s, 2H), 3.98-4.07 (m, 2H), 3.83-3.90 (m, 2H),3.54-3.58 (m, 4H), 3.22 (p, J=15.0, 7.3, 1H), 2.89-2.93 (m, 4H),2.10-2.30 (m, 4H).

The compounds in Examples 57-65 were prepared using methods analogous tothose described in the preceding examples.

Example 574-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.1; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.87 (s, 1H), 4.84 (br s, 2H), 3.98-4.06 (m, 2H), 3.83-3.89(m, 2H), 3.58-3.61 (m, 4H), 3.17-3.25 (m, 1H), 2.42-2.46 (m, 4H), 2.32(s, 3H), 2.20-2.29 (m, 1H), 2.08-2.18 (m, 1H).

Example 584-Piperazin-1-yl-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.17; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.80 (s, 1H), 5.16 (br s, 2H), 4.03-4.08 (m, 2H), 3.56-3.60(m, 4H), 3.50 (dt, J=11.4, 3.0, 2H), 2.90-2.94 (m, 4H), 2.58-2.67 (m,1H), 1.73-1.85 (m, 4H).

Example 594-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.19; m/z found, 278.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.81 (s, 1H), 4.74 (br s, 2H), 4.05 (dt, J=11.2, 3.2, 2H),3.59-3.62 (m, 4H), 3.45-3.52 (m, 2H), 2.54-2.62 (m, 1H), 2.43-2.46 (m,4H), 2.33 (s, 3H), 1.76-1.82 (m, 4H).

Example 60(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.19; m/z found, 278.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.60 (s, 1H), 4.72 (br s, 2H), 4.03-4.08 (m, 2H), 3.30-3.70(m, 7H), 2.53-2.61 (m, 1H), 2.48 (s, 3H), 2.11-2.20 (m, 1H), 1.73-1.86(m, 5H).

Example 61(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅O, 303.21; m/z found, 304.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.60 (br s, 1H), 5.1-5.5 (br s, 2H), 4.02-4.08 (m, 2H),3.02-3.57 (m, 6H), 2.96-3.04 (m, 1H), 2.58-2.70 (m, 2H), 2.22-2.42 (m,1H), 1.48-1.88 (m, 8H).

Example 62 4-Benzyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.35; m/z found, 270.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.22-7.35 (m, 5H), 5.68-5.75 (br s, 2H), 5.66 (s, 1H),3.9-4.10 (br s, 1H), 3.84 (s, 2H), 3.48-3.54 (m, 4H), 2.85-2.90 (m, 4H).

Example 63 4-Benzyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.37; m/z found, 284.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.20-7.32 (m, 5H), 5.73 (s, 1H), 4.75 (br s, 2H), 3.78 (s,2H), 3.5-3.55 (m, 4H), 2.38-2.45 (m, 4H), 2.32 (s, 3H).

Example 64(R)-Benzyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.37; m/z found, 284.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.18-7.32 (m, 5H), 5.50 (s, 1H), 4.83-4.85 (br s, 2H), 3.78(s, 3H), 3.2-3.7 (m, 4H), 2.44 (s, 3H), 2.05-2.15 (m, 1H), 1.74-1.84 (m,1H).

Example 65(R,R)-4-Benzyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.41; m/z found, 310.2 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.90-12.95 (br s, 1H), 10.10-10.22 (m, 1H), 9.0-9.10 (m,1H), 7.25-7.45 (m, 5H), 6.24 (s, 1H), 3.65-3.95 (br m, 6H), 3.48-3.58(m, 1H), 3.12-3.16 (m, 1H), 2.60-2.90 (m, 2H), 1.60-1.80 (m, 4H).

Example 664-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

Steps A: 4-Chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine. The titlecompound was prepared from 3-cyclohexyl-3-oxo-propionic acid ethylester, using methods analogous to those described in Example 1, StepsA-B.

Step B:4-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine. Asolution of 4-chloro-5,6,7,8-tetrahydro-quinazolin-2-ylamine (100 mg,0.55 mmol), N-methyl piperazine (91 uL, 1.5 mmol) and Et₃N (140 uL, 1.1mmol) in EtOH (2 ml) was heated at 70° C. for 16 h. The mixture wascooled to rt and concentrated, and the crude residue was purified (2 MNH₃ in MeOH/CH₂Cl₂) to yield a white solid (31 mg, 23%). MS (ESI): masscalcd. for C₁₃H₂₁N₅, 247.3; m/z found, 248.2 [M+H]⁺. ¹H NMR (MeOD):3.30-3.23 (m, 4H), 3.21 (dt, J=3.3, 1.6, 1H), 2.49 (t, J=6.7, 2H),2.47-2.41 (m, 4H), 2.36 (t, J=5.9, 2H), 2.23 (s, 3H), 1.77-1.67 (m, 2H),1.62-1.52 (m, 2H).

The compounds in Examples 67-75 were prepared using methods analogous tothose described in Example 66.

Example 67 4-(4-Piperazin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺. ¹HNMR (MeOD): 3.28-3.20 (m, 4H), 2.85 (t, J=4.8, 4H), 2.53 (t, J=6.6, 2H),2.39 (t, J=5.9, 2H), 1.80-1.71 (m, 2H), 1.65-1.56 (m, 2H).

Example 68(R)-4-(3-Amino-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.2; m/z found, 234.2 [M+H]⁺.

Example 69(R)-4-(3-Methylamino-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 248.4; m/z found, 248.2 [M+H]⁺. ¹HNMR (MeOD): 3.67-3.55 (m, 2H), 3.53-3.45 (m, 1H), 3.28 (dd, J=11.0, 5.5,1H), 3.06 (p, J=6.0, 1H), 2.58-2.45 (m, 2H), 2.38 (t, J=6.4, 2H), 2.24(s, 3H) 2.01-1.90 (m, 1H), 1.68-1.45 (m, 5H).

Example 70 (R,R)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅, 259.2; m/z found, 260.2 [M+H]⁺.

Example 714-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.4; m/z found, 274.3 [M+H]⁺. ¹HNMR (MeOD): 3.87-3.74 (m, 2H), 3.66-3.59 (m, 1H), 3.54 (dd, J=11.7, 1.6,1H), 3.32-3.28 (m, 1H), 2.96 (dt, J=12.2, 3.6, 1H), 2.78-2.68 (m, 2H),2.67-2.58 (m, 1H), 2.58-2.50 (m, 2H), 2.34-2.24 (m, 1H), 1.92-1.80 (m,2H), 1.80-1.73 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.44 (m, 2H).

Example 72(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.4; m/z found, 274.3 [M+H]⁺. ¹HNMR (MeOD): 3.87-3.74 (m, 2H), 3.66-3.59 (m, 1H), 3.54 (dd, J=11.7, 1.6,1H), 3.32-3.28 (m, 1H), 2.96 (dt, J=12.2, 3.6, 1H), 2.78-2.68 (m, 2H),2.67-2.58 (m, 1H), 2.58-2.50 (m, 2H), 2.34-2.24 (m, 1H), 1.92-1.80 (m,2H), 1.80-1.73 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.44 (m, 2H).

Example 73(S,S)-4-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₉N₅, 245.2; m/z found, 246.2 [M+H]⁺.

Example 744-(4-Methyl-piperazin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 4.75 (s, 2H), 3.68 (t, J=9.8, 4.8, 4H), 2.91-2.85 (t,J=14.4, 7.0, 2H), 2.73-2.66 (t, J=15.6, 7.7, 2H), 2.47-2.42 (t, J=10.0,5.0, 4H), 2.31 (s, 3H), 2.03-1.94 (qt, J=15.5, 7.9, 2H).

Example 75(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.16; m/z found, 234.2 [M+H]⁺. ¹HNMR (CDCl₃): 4.88 (s, 2H), 3.84-3.74 (m, 2.7H), 3.72-3.61 (m, 1.3H),3.49-3.41 (m, 2H), 3.27-3.20 (m, 1H), 3.08-2.92 (m, 2H), 2.82-2.61 (m,2H), 2.46 (s, 3H), 2.14-2.04 (m, 1H), 2.02-1.90 (m, 2H), 1.83-1.74 (m,2H).

The compounds in Examples 76-79 were prepared using methods analogous tothose described in the preceding examples.

Example 76 4-tert-Butyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺.

Example 77 4-tert-Butyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.3 [M+H]⁺.

Example 78(R)-4-tert-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.3 [M+H]⁺.

Example 79(R,R)-4-tert-Butyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.3 [M+H]⁺.

Intermediate 1: 3-(4-Methyl-tetrahydro-pyran-4-yl)-3-oxo-propionic acidethyl ester

Step A: (4-Methyl-tetrahydro-pyran-4-yl)-methanol. A −78° C. solution of4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (Regan, J. etal. J. Med. Chem. 2002, 45, 2994-3008; 9.9 g, 63 mmol) in CH₂Cl₂ (400mL) was treated with DIBAL-H (1.0 M in CH₂Cl₂; 125 mL, 125 mmol). Theresulting mixture was stirred for 1 h, and then was diluted with EtOAc(200 mL) and satd. aq. NH₄Cl. The mixture was treated with satd. aq.sodium potassium tartrate, allowed to warm to rt, and stirred for 45min. The mixture was extracted with CH₂Cl₂ (4×), and the combinedextracts were washed with satd. aq. NaCl, dried, and concentrated.Chromatography (EtOAc/hexanes) afforded the title compound as acolorless oil (5.6 g 69%). The spectral data matched that reported inPCT Intl. Pat. Appl. Publ. No. WO 2006/001752.

Step B: 4-Methyl-tetrahydro-pyran-4-carboxaldehyde. To a solution of(4-methyl-tetrahydro-pyran-4-yl)-methanol (1.5 g, 11.5 mmol) in CH₂Cl₂was added a suspension of Dess-Martin periodinane (5.8 g, 14 mmol) inCH₂Cl₂ (30 mL). After 70 min, the heterogenous mixture was diluted withEt₂O (100 mL), stirred for 10 min, treated with 1 N HaOH (10 mL), andstirred for another 10 min. The mixture was filtered, and the filtratewas concentrated. The residue was purified by chromatography(Et₂O/CH₂Cl₂) to give the title compound (1.01 g, 68%) as a colorlessvolatile oil. The spectral data matched that reported in PCT Intl. Pat.Appl. Publ. No. WO 2006/001752.

Step C: 3-(4-Methyl-tetrahydro-pyran-4-yl)-3-oxo-propionic acid ethylester. To a solution of BF₃.OEt₂ (0.350 mL, 2.50 mmol) and ethyldiazoacetate (0.390 mL, 3.42 mmol) was added a solution of4-methyl-tetrahydro-pyran-4-carboxaldehyde (350 mg, 2.73 mmol) in CH₂Cl₂(15 mL). After 20 min, the mixture was poured into half-saturated aq.NaCl and extracted with CH₂Cl₂. The combined organic layers were driedand concentrated. Chromatography (EtOAc/hexanes) afforded the titlecompound (461 mg, 79%) as a colorless oil. MS (ESI): mass calcd. forC₁₁H₁₈O₄, 214.1; m/z found, 215.2 [M+H]⁺. ¹H NMR (mixture of tautomers;CDCl₃): 12.5 (s, 0.5H), 5.05 (s, 0.5H), 4.25-4.17 (m, 2H), 3.76-3.53 (m,2H), 5.52 (s, 3H), 2.05-1.92 (m, 2H), 1.56-1.47 (m, 2H), 1.26-1.22 (m,3H), 1.38-1.34 (m, 3H).

Intermediate 2: 3-Cyclopentyl-2-methoxy-3-oxo-propionic acid methylester

The title compound was prepared using a method analogous to thatdescribed in Tetrahedron 1998, 44, 1603-1607: To a suspension ofiodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was addedBF₃.OEt₂ (2.1 mL, 16.3 mmol). The resulting mixture was added to3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) andstirred at rt overnight. The mixture was concentrated to half the totalvolume, quenched with satd. aq. NaHCO₃, and extracted with CHCl₃ (2×).The combined organic layers were dried and concentrated and the cruderesidue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%).¹H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H),1.9-1.5 (m, 8H).

Intermediate 3: 3-Oxo-4-pyridin-4-yl-butyric acid ethyl ester

A solution of pyridin-4-yl-acetic acid hydrochloride salt (1.73 g 10mmol) in CH₂Cl₂ (50 mL) was treated with triethylamine (2.09 mL, 15mmol), followed by 1,1′-carbonyldiimidazole (2.43 g, 15 mol). After 4 h,the solution was added dropwise to a 0° C. solution of2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid; 1.73 g, 12 mmol)and pyridine (1.63 mL, 20 mmol) in CH₂Cl₂ (50 mL). The reaction mixturewas allowed to warm slowly to rt and was stirred for 18 h. The mixturewas washed with H₂O (2×), and the organic layer was dried andconcentrated. The crude residue was dissolved in EtOH (100 mL) andheated at reflux for 4 h. The mixture was allowed to cool to rt and wasconcentrated. The residue was purified by chromatography (EtOAc/hexanes)to give the title compound (411 mg, 15%) as a pale yellow oil. MS (ESI):mass calcd. for C₁₁H₁₃NO₃, 207.1; m/z found, 208.1 [M+H]⁺. ¹H NMR(CDCl₃): 8.57 (dd, J=4.4, 1.6, 2H), 7.16 (dd, J=4.4, 1.6, 2H), 4.20 (q,J=7.2, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 1.28 (t, J=7.2, 3H).

Intermediate 4: 3-Oxo-3-(tetrahydro-furan-3-yl)-propionic acid ethylester

To a solution of lithium bis(trimethylsilyl)amide (1 M in hexanes; 100mL) in THF (200 mL) at ˜78° C. was added dry ethyl acetate (10.8 g, 12mL, 122.5 mmol) dropwise. After 30 min at ˜78° C., the mixture wastreated with a solution of tetrahydro-furan-3-carboxylic acid methylester (6.0 g, 46.1 mmol) in THF (50 mL). After 4 h at −78° C., thereaction was quenched with satd. aq. NH₄Cl, warmed to rt, and extractedwith EtOAc (5×75 mL). The combined organic layers were washed with satd.aq. NaCl, dried, and concentrated to give a colorless oil.Chromatography on SiO₂ (EtOAc/CH₂Cl₂) afforded the title compound (3.3g).

The compounds in Examples 80-255 were prepared from the appropriatebeta-ketoesters according to methods described in the precedingexamples. The beta-ketoesters or 1,3-diones used were commerciallyavailable or prepared using methods described for Intermediates 1-4.

Example 80(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅, 247.2; m/z found, 248.2 [M+H]⁺. ¹HNMR (MeOD): 5.72 (s, 1H), 3.85-3.54 (m, 3H), 3.54-3.32 (m, 1H),3.32-3.15 (m, 1H), 2.92-2.71 (m, 1H), 2.24 (ddd, J=12.8, 12.7, 6.4, 1H),2.03-1.94 (m, 2H), 1.95-1.75 (m, 3H), 1.74-1.63 (m, 4H).

Example 81(R,R)-4-Cyclopentyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.2; m/z found, 288.3 [M+H]⁺. ¹HNMR (MeOD): 5.77-5.68 (m, 1H), 3.65-3.25 (m, 5H), 2.91 (td, J=12.3, 3.8,1H), 2.86-2.74 (m, 1H), 2.66-2.55 (m, 1H), 2.47-2.25 (m, 1H), 2.05-1.89(m, 2H), 1.88-1.73 (m, 4H), 1.75-1.58 (m, 4H), 1.54-1.44 (m, 1H).

Example 824-Cyclopentyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.2; m/z found, 288.3 [M+H]⁺. ¹HNMR (CDCl₃): 5.77 (s, 1H), 3.64-3.56 (m, 2H), 3.46-3.37 (m, 3H),3.04-2.95 (m, 2H), 2.85-2.75 (m, 2H), 2.44 (dd, J=9.8, 4.1, 2H), 2.32(s, 3H), 2.03-1.92 (m, 2H), 1.84-1.75 (m, 2H), 1.73-1.62 (m, 4H).

Example 83(R,R)-4-Cyclopentyl-6-(hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.2; m/z found, 274.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.63 (s, 1H), 5.36-5.13 (m, 2H), 3.97-3.85 (m, 1H),3.78-3.63 (m, 1H), 3.64-3.54 (m, 1H), 3.56-3.42 (m, 1H), 3.38-3.22 (m,1H), 3.20-3.04 (m, 2H), 3.05-2.92 (m, 2H), 2.92-2.75 (m, 2H), 2.11-1.89(m, 3H), 1.86-1.57 (m, 7H).

Example 844-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅, 287.2; m/z found, 288.2 [M+H]⁺. ¹HNMR (MeOD): 5.72 (s, 1H), 3.68-3.27 (m, 4H), 3.07-2.88 (m, 2H),2.85-2.74 (m, 1H), 2.08-1.92 (m, 4H), 1.93-1.74 (m, 6H), 1.74-1.57 (m,4H).

Example 85 4-(3-Amino-azetidin-1-yl)-6-cyclopentyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅, 233.16; m/z found, 234.3 [M+H]⁺. ¹HNMR (MeOD): 10.97-8.73 (br. s, 3H), 7.73 (s, 2H), 5.98 (s, 1H), 4.38 (s,2H), 4.30-4.07 (m, 3H), 2.96-2.84 (m, 1H), 2.11-1.89 (m, 2H), 1.89-1.71(m, 2H), 1.73-1.52 (m, 4H).

Example 864-Cyclopentyl-6-(trans-hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₃N₅O, 289.2; m/z found, 290.2 [M+H]⁺. ¹HNMR (MeOD): 5.62 (s, 1H), 4.72 (s, 2H), 3.99 (dd, J=11.7, 2.5, 2H), 3.77(dt, J=11.7, 2.9, 1H), 3.67-3.49 (m, 2H), 3.20 (t, J=9.8, 1H), 3.13-3.03(m, 2H), 2.98 (dd, J=12.3, 1.9, 2H), 2.86-2.76 (m, 1H), 2.07-1.91 (m,4H), 1.83-1.57 (m, 4H).

Example 874-Cyclopentyl-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅, 273.2; m/z found, 274.3 [M+H]⁺.

Example 884-Cyclopentyl-6-(cis-hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅O, 289.19; m/z found, 290.2 [M+H]⁺.

Example 89 (2-Amino-ethyl)-6-isopropyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₉H₁₇N₅, 195.15; m/z found, 196.2 [M+H]⁺. ¹HNMR (MeOD): 8.11 (s, 1H), 6.04 (s, 1H), 3.75 (t, J=5.8, 2H), 3.21 (t,J=5.8, 2H), 2.81 (td, J=13.7, 6.8, 1H), 1.29 (d, J=6.9, 6H).

Example 90 4-(3-Amino-azetidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅, 207.3; m/z found, 208.3 [M+H]⁺. ¹HNMR (CDCl₃): 12.95 (s, 1H), 8.87 (s, 3H), 8.29-7.56 (br s, 2H), 6.01 (s,1H), 4.47 (dd, J=9.9, 8.0, 1H), 4.36 (dd, J=10.3, 8.0, 1H), 4.27 (dd,J=10.5, 4.2, 1H), 4.20 (dd, J=10.9, 4.4, 1H), 4.17-4.09 (m, 1H), 2.81(td, J=13.8, 6.9, 1H), 1.24 (d, J=6.9, 6H).

Example 914-(1,7-Diaza-spiro[4.4]non-7-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.2; m/z found, 262.1 [M+H]⁺. ¹HNMR (CDCl₃): 5.52 (s, 1H), 4.63 (s, 2H), 3.59-3.20 (m, 4H), 3.02-2.90(m, 2H), 2.58 (td, J=13.8, 6.9, 1H), 1.95-1.85 (m, 2H), 1.85-1.65 (m,4H), 1.14 (d, J=6.9, 6H).

Example 92N⁴-(2-Amino-ethyl)-6-isopropyl-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₀H₁₉N₅, 209.16; m/z found, 210.2 [M+H]⁺.

Example 934-(cis-Hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.17; m/z found, 264.2 [M+H]⁺.

Example 944-(trans-Hexahydro-pyrrolo[3,4-b][1,4]oxazin-6-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.17; m/z found, 264.2 [M+H]⁺.

Example 95 4-Isopropyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 263.17; m/z found, 264.2 [M+H]⁺.

Example 964-(4-Methyl-piperazin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 249.16; m/z found, 250.3 [M+H]⁺. ¹HNMR (CDCl₃): 4.69 (s, 2H), 4.50 (s, 2H), 4.00 (t, J=6.1,Hz, 2H),3.32-3.28 (m, 4H), 2.74 (t, J=6.1,Hz, 2H), 2.50-2.45 (m, 4H), 2.33 (s,3H).

Example 97(R,R)-4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅O, 275.2; m/z found, 276.3 [M+H]⁺. ¹HNMR (DMSO-d₆): 12.97-12.63 (br s, 1H), 9.99 (s, 1H), 9.34 (s, 1H), 7.62(s, 2H), 4.95-4.79 (m, 1H), 4.74 (d, J=13.5, 1H), 4.05-3.63 (m, 7H),3.16 (d, J=12.1, 1H), 2.91-2.57 (m, 4H), 1.95-1.56 (m, 4H).

Example 98(R)-4-(3-Amino-pyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅O, 235.14; m/z found, 236.2 [M+H]⁺.

Example 99(R)-4-(3-Methylamino-pyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 249.16; m/z found, 250.3 [M+H]⁺.

Example 1004-Piperazin-1-yl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅O, 235.14; m/z found, 236.2 [M+H]⁺.

Example 101 4-Butyl-5-methoxy-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.2; m/z found, 266.1 [M+H]⁺. ¹HNMR (MeOD): 4.30 (s, 4H), 3.69 (s, 3H), 3.43-3.37 (m, 4H), 2.73-2.66 (m,2H), 1.68 (td, J=15.5, 7.6, 2H), 1.51-1.39 (m, 2H), 0.99 (t, J=7.3, 3H).

Example 102 4-Butyl-6-[1,4]diazepan-1-yl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.21; m/z found, 280.2 [M+H]⁺.

Example 1034-(3-Amino-azetidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2; m/z found, 252.2 [M+H]⁺.

Example 104(R)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁H₂₃N₅O, 265.2; m/z found, 266.1 [M+H]⁺.

Example 105(S)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁H₂₃N₅O, 265.2; m/z found, 266.1 [M+H]⁺.

Example 106(R)-4-Butyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.2; m/z found, 280.2 [M+H]⁺.

Example 107(S)-4-Butyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.2; m/z found, 280.2 [M+H]⁺.

Example 1084-Butyl-5-methoxy-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₅N₅O, 279.2; m/z found, 280.2 [M+H]⁺.

Example 109N⁴-(2-Amino-ethyl)-6-butyl-5-methoxy-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₂H₂₃N₅O, 253.2; m/z found, 254.2 [M+H]⁺.

Example 110 N⁴-(2-Amino-ethyl)-6-butyl-5-methoxy-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₂₁N₅O, 239.2; m/z found, 240.2 [M+H]⁺.

Example 1114-(3-Amino-azetidin-1-yl)-6-cyclopentyl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 263.2; m/z found, 264.2 [M+H]⁺. ¹HNMR (MeOD): 4.97-4.88 (m, 1H), 4.64-4.52 (m, 2H), 4.33-4.23 (m, 2H),3.70 (s, 3H), 3.48-3.35 (m, 1H), 2.11-2.01 (m, 2H), 1.99-1.89 (m, 2H),1.84-1.67 (m, 4H).

Example 1124-Cyclopentyl-6-[1,4]diazepan-1-yl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅O, 291.2; m/z found, 292.2 [M+H]⁺. ¹HNMR (MeOD): 4.33-3.99 (m, 4H), 3.69 (s, 3H), 3.58-3.44 (m, 3H),3.41-3.34 (m, 2H), 2.27-2.17 (m, 2H), 2.16-2.03 (m, 2H), 2.02-1.91 (m,2H), 1.86-1.66 (m, 4H).

Example 113(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopentyl-5-methoxy-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, 278.2 [M+H]⁺.

Example 114(S)-4-Cyclopentyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 291.2; m/z found, 292.2 [M+H]⁺.

Example 115N⁴-(2-Amino-ethyl)-6-cyclopentyl-5-methoxy-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.2; m/z found, 266.2 [M+H]⁺.

Example 116N⁴-(2-Amino-ethyl)-6-cyclopentyl-5-methoxy-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2; m/z found, 252.2 [M+H]⁺.

Example 117 4-[1,4]Diazepan-1-yl-6-methoxymethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₉N₅O, 237.2; m/z found, 238.2 [M+H]⁺. ¹HNMR (MeOD): 6.50 (s, 1H), 4.48-4.42 (m, 2H), 4.24-4.17 (m, 1.5H),4.11-3.99 (m, 1.5H), 3.86-3.77 (m, 1.5H), 3.48 (s, 3H), 3.46-3.41 (m,1.5H), 3.41-3.33 (m, 2H), 2.29-2.12 (m, 2H).

Example 118(S)-4-(3-Amino-pyrrolidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.14; m/z found, 224.2 [M+H]⁺.

Example 119(S)-4-Methoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 237.2; m/z found, 238.2 [M+H]⁺.

Example 1204-Cyclopropyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅, 259.18; m/z found, 260.3 [M+H]⁺. ¹HNMR (CDCl₃): 5.60 (s, 1H), 4.66 (s, 2H), 3.67-3.54 (m, 2H), 3.42-3.31(m, 2H), 2.98-2.88 (m, 2H), 2.73-2.67 (m, 2H), 2.45-2.36 (m, 2H), 2.32(s, 3H), 1.71-1.65 (m, 1H), 0.98-0.90 (m, 2H), 0.90-0.82 (m, 2H).

Example 121 4-Cyclopropyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.15; m/z found, 220.3 [M+H]⁺. ¹HNMR (MeOD): 6.21 (s, 1H), 4.32-3.88 (m, 4H), 3.36-3.32 (m, 4H),1.97-1.89 (m, 1H), 1.27-1.20 (m, 2H), 1.13-1.08 (m, 2H).

Example 122 4-(3-Amino-azetidin-1-yl)-6-cyclopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₅N₅, 205.13; m/z found, 206.3 [M+H]⁺. ¹HNMR (MeOD): 4.34-4.19 (m, 4H), 1.92-1.86 (m, 1H), 1.25-1.17 (m, 2H),1.12-1.06 (m, 2H).

Example 123(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.15; m/z found, 220.3 [M+H]⁺. ¹HNMR (MeOD): 5.93 (s, 0.6H), 5.91 (s, 0.4H), 4.15-3.59 (m, 5H), 2.60-2.36(m, 1H), 2.31-2.09 (m, 1H), 1.98-1.87 (m, 1H), 1.27-1.19 (m, 2H),1.11-1.04 (m, 2H).

Example 1244-Cyclopropyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₉N₅, 245.16; m/z found, 246.3 [M+H]⁺. ¹HNMR (MeOD): 5.92 (s, 1H), 3.98-3.73 (m, 3H), 3.72-3.54 (m, 3H),3.34-3.20 (m, 4H), 2.00-1.89 (m, 1H), 1.25-1.17 (m, 2H), 1.15-1.07 (m,2H).

Example 125(S)-4-Isopropyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.3 [M+H]⁺. ¹HNMR (CDCl₃): 5.59 (s, 1H), 5.03 (s, 2H), 3.77-3.14 (m, 5H), 2.65-2.49(m, 1H), 2.47 (s, 3H), 2.21-2.08 (m, 1H), 1.91-1.75 (m, 1H), 1.21 (s,3H), 1.19 (s, 1H).

Example 126(S)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.16; m/z found, 222.3 [M+H]⁺. ¹HNMR (MeOD): 6.32-6.26 (m, 1H), 4.36-4.14 (m, 2H), 4.13-3.86 (m, 3H),3.09 (q, J=6.9, 1H), 2.81-2.60 (m, 1H), 2.54-2.33 (m, 1H), 1.53 (d,J=6.9, 6H).

Example 127(R)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.3 [M+H]⁺. ¹HNMR (MeOD): 6.11-5.99 (m, 1H), 4.22-3.96 (m, 2H), 3.95-3.70 (m, 3H),2.64-2.40 (m, 1H), 2.39-2.12 (m, 1H), 1.40 (s, 9H).

Example 1284-tert-Butyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.73 (s, 1H), 4.82 (s, 1H), 3.66-3.57 (m, 2H), 3.43-3.34(m, 2H), 2.96-2.90 (m, 2H), 2.73-2.66 (m, 2H), 2.47-2.41 (m, 2H), 2.32(s, 3H), 1.23 (s, 9H).

Example 129(S)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (MeOD): 6.11-5.99 (m, 1H), 4.22-3.96 (m, 2H), 3.95-3.70 (m, 3H),2.64-2.40 (m, 1H), 2.39-2.12 (m, 1H), 1.40 (s, 9H).

Example 130(S)-4-tert-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.71 (s, 1H), 4.80 (s, 1H), 3.72-3.51 (m, 2H), 3.49-3.40(m, 1H), 3.38-3.22 (m, 2H), 2.47 (s, 3H), 2.21-2.10 (m, 1H), 1.91-1.76(m, 1H), 1.25 (s, 9H).

Example 131N⁴-(2-Amino-ethyl)-6-tert-butyl-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₂₁N₅, 223.18; m/z found, 224.4 [M+H]⁺.

Example 1324-tert-Butyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.20; m/z found, 262.3 [M+H]⁺.

Example 133 4-(3-Amino-azetidin-1-yl)-6-tert-butyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.16; m/z found, 222.3 [M+H]⁺.

Example 1344-tert-Butyl-6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.20; m/z found, 262.3 [M+H]⁺.

Example 135 (R)-4-(3-Amino-pyrrolidin-1-yl)-6-butyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (MeOD): 6.17-6.13 (m, 1H), 4.17-3.95 (m, 2H), 3.94-3.69 (m, 3H),2.66-2.57 (m, 2H), 2.59-2.42 (m, 1H), 2.36-2.17 (m, 1H), 1.75-1.65 (m,2H), 1.43-1.40 (m, 2H), 0.98 (t, J=7.4, 3H).

Example 136 4-Butyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.81 (s, 1H), 4.91 (s, 2H), 3.59 (t, J=4.9, 4H), 2.47-2.39(m, 6H), 2.32 (s, 3H), 1.66-1.56 (m, 2H), 1.42-1.31 (m, 2H), 0.92 (t,J=7.34, 3H).

Example 137(R)-4-Butyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.57 (s, 1H), 5.22 (s, 2H), 3.75-3.07 (m, 5H), 2.45 (s,3H), 2.43-2.38 (m, 2H), 2.18-2.08 (m, 1H), 1.88-1.73 (m, 1H), 1.66-1.55(m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.3, 3H).

Example 138 N⁴-(2-Amino-ethyl)-6-butyl-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 223.18; m/z found, 224.2 [M+H]⁺. ¹HNMR (MeOD): 6.29 (s, 1H), 4.04 (t, J=5.6, 2H), 3.36 (s, 3H), 3.31-3.27(m, 2H), 3.27-3.23 (m, 3H), 2.69-2.61 (m, 2H), 1.76-1.65 (m, 2H),1.49-1.38 (m, 2H), 0.98 (t, J=7.3, 3H).

Example 1394-Butyl-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.61 (s, 1H), 4.89 (s, 2H), 3.67-3.57 (m, 2H), 3.42-3.32(m, 2H), 2.98-2.88 (m, 2H), 2.72-2.65 (m, 2H), 2.48-2.38 (m, 4H), 2.32(s, 3H), 1.66-1.56 (m, 2H), 1.36-1.29 (m, 2H), 0.92 (t, J=7.3, 3H).

Example 140Butyl-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.20; m/z found, 262.2 [M+H]⁺. ¹HNMR (MeOD): 6.12 (s, 1H), 3.98-3.76 (m, 3H), 3.72-3.56 (m, 3H),3.41-3.32 (m, 2H), 3.29-3.22 (m, 2H), 2.65-2.57 (m, 1H), 1.75-1.64 (m,2H), 1.43-1.31 (m, 2H), 0.98 (t, J=7.3, 1H).

Example 1414-Butyl-6-(cis-octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 275.21; m/z found, 276.2 [M+H]⁺. ¹HNMR (MeOD): 6.15 (s, 1H), 4.15-4.04 (m, 1H), 4.01-3.76 (m, 3H),3.69-3.58 (m, 1H), 3.40-3.32 (m, 1H), 3.14-3.01 (m, 1H), 3.00-2.77 (m,1H), 2.66-2.59 (m, 2H), 2.03-1.78 (m, 4H), 1.76-1.65 (m, 2H), 1.49-1.38(m, 2H), 1.02-0.96 (m, 3H).

Example 142 4-Butyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (MeOD): 6.49 (s, 1H), 4.35-3.97 (m, 4H), 3.45-3.34 (m, 4H),2.68-2.60 (m, 2H), 1.76-1.65 (m, 2H), 1.50-1.38 (m, 2H), 0.98 (t, J=7.4,3H).

Example 1434-Butyl-6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.20; m/z found, 262.3 [M+H]⁺. ¹HNMR (MeOD): 5.76 (s, 1H), 4.44-3.71 (m, 4H), 3.22-2.93 (m, 2H),2.48-2.38 (m, 2H), 2.05-1.85 (m, 2H), 1.75-1.56 (m, 3H), 1.43-1.29 (m,2H), 0.96-0.89 (m, 3H).

Example 144 4-(4-Methyl-piperazin-1-yl)-6-propyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.81 (s, 1H), 4.78 (s, 2H), 3.59 (t, J=4.6, 3H), 2.58-2.50(m, 1H), 2.47-2.36 (m, 7H), 2.32 (s, 3H), 1.72-1.61 (m, 2H), 0.99-0.92(m, 3H).

Example 1454-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-propyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅, 261.20; m/z found, 262.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.62 (s, 1H), 4.68 (s, 2H), 3.68-3.58 (m, 2H), 3.42-3.32(m, 2H), 2.99-2.89 (m, 2H), 2.72-2.64 (m, 2H), 2.48-2.37 (m, 4H), 2.32(s, 3H), 1.70-1.61 (m, 2H), 0.95 (t, J=7.4, 3H).

Example 146 4-Isobutyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.77 (s, 1H), 4.98 (s, 2H), 3.62-3.56 (m, 4H), 2.47-2.42(m, 4H), 2.32 (s, 3H), 2.30 (s, 1H), 2.28 (s, 1H), 2.04-1.96 (m, 1H),0.92 (d, J=6.6, 6H).

Example 147 4-Isobutyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (MeOD): 5.95 (s, 1H), 3.63-3.58 (m, 4H), 3.50-3.43 (m, 4H),3.32-3.30 (m, 1H), 2.29 (s, 1H), 2.28 (s, 1H), 2.06-1.95 (m, 1H), 0.92(d, J=6.6, 6H).

Example 148(R)-4-Isobutyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅, 249.20; m/z found, 250.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.56 (s, 1H), 5.00 (s, 2H), 3.72-3.09 (m, 5H), 2.47 (s,3H), 2.29 (s, 1H), 2.27 (s, 1H), 2.20-2.10 (m, 1H), 2.09-1.99 (m, 1H),0.92 (d, J=6.6, 6H).

Example 149(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isobutyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅, 235.18; m/z found, 236.2 [M+H]⁺. ¹HNMR (MeOD): 6.15 (s, 0.7H), 6.14 (s, 0.3H), 4.18-3.64 (m, 5H), 2.50 (s,1H), 2.48 (s, 1H), 2.34-2.14 (m, 1H), 2.12-2.00 (m, 1H), 1.00 (d, J=6.6,6H).

Example 150(S)-4-Ethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅, 221.16; m/z found, 222.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.61 (s, 1H), 5.21 (s, 2H), 3.72-3.12 (m, 5H), 2.55-2.41(m, 5H), 2.22-2.09 (m, 1H), 1.93-1.77 (m, 1H), 1.27-1.15 (t, J=7.3, 3H).

Example 151(R)-4-Adamantan-1-yl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₉H₂₉N₅, 327.24; m/z found, 328.4 [M+H]⁺. ¹HNMR (CDCl₃): 5.92 (s, 1H), 4.71 (s, 2H), 3.71-3.17 (m, 5H), 2.48 (s,3H), 1.99-1.92 (m, 6H), 1.81-1.72 (m, 6H), 1.38 (s, 1H), 1.15 (s, 1H).

Example 1524-Adamantan-1-yl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₉H₂₉N₅, 327.24; m/z found, 328.4 [M+H]⁺. ¹HNMR (CDCl₃): 5.88 (s, 1H), 4.74 (s, 2H), 3.60 (t, J=5.1, 4H), 2.45 (t,J=5.1, 4H), 2.34-2.31 (m, 3H), 2.08-2.03 (m, 3H), 1.91-1.88 (m, 6H),1.79-1.69 (m, 6H), 1.38 (s, 1H), 1.12 (s, 1H).

Example 1534-(4-Methyl-tetrahydro-pyran-4-yl)-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, [M+H]⁺.=278.2. ¹HNMR (CDCl₃): 5.87 (s, 1H), 4.79 (br s, 2H), 3.76-3.71 (m, 2H), 3.63-3.50(m, 6H), 2.95-2.87 (m, 4H), 2.18-2.10 (m, 2H), 2.05-1.85 (m, 1H),1.66-1.60 (m, 2H), 1.23 (s, 3H). The free base was treated with HCl (4 Min 1,4-dioxane; 2 equiv.) in CH₂Cl₂ to provide the bis-HCl salt (227 mg)as a white solid.

Example 1544-(4-Methyl-piperazin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅O, 291.2; m/z found, 292.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.89 (s, 1H), 4.80-4.50 (m, 2H), 3.78-3.70 (m, 2H),3.65-3.55 (m, 5H), 2.50-2.40 (m, 4H), 2.33 (s, 3H), 2.20-2.10 (m, 2H),1.84-1.58 (br m, 3H), 1.23 (s, 3H).

Example 155(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅, 291.2; m/z found, 292.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.66 (s, 1H), 4.66 (br s, 2H), 3.79-3.70 (m, 2H), 3.65-3.50(m, 4H), 3.50-3.39 (m, 1H), 3.38-3.20 (m, 2H), 2.48 (s, 3H), 2.22-2.12(m, 3H), 1.90-1.78 (1H), 1.68-1.58 (m, 2H), 1.22 (s, 3H).

Example 1564-(trans-2-Phenyl-cyclopropyl)-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₁N₅, 295.2; m/z found, 296.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.24 (m, 2H), 7.19-7.10 (m, 3H), 5.86 (s, 1H), 4.79(br s, 2H), 3.56-3.52 (m, 4H), 2.90-2.80 (m, 4H), 2.50-2.45 (m, 1H),2.45-2.27 (m, 1H), 2.09-1.94 (m, 1H), 1.77-1.70 (m, 1H), 1.39-1.31 (m,1H).

Example 157(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₁N₅, 295.2; m/z found, 296.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.29-7.25 (m, 2H), 7.20-7.10 (m, 3H), 5.62 (s, 1H),5.29-5.19 (br s, 2H), 3.78-3.34 (4H), 3.30-3.01 (m, 1H), 2.62-2.26 (m,2H), 2.25-2.07 (m, 1H), 2.05-1.95 (m, 2H), 1.84-1.66 (m, 2H), 1.40-1.33(m, 1H).

Example 1584-(4-Methyl-piperazin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.2; m/z found, 310.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.23 (m, 2H), 7.19-7.09 (m, 3H), 5.89 (s, 1H), 4.64(br s, 2H), 3.63-3.55 (m, 4H), 2.51-2.45 (m, 1H), 2.44-2.40 (m, 4H),2.31 (s, 3H), 1.99-1.94 (m, 1H), 1.75-1.70 (m, 1H), 1.37-1.30 (m, 1H).

Example 159N⁴-(2-Amino-ethyl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.2; m/z found, 270.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.30-7.26 (m, 2H), 7.24-7.18 (m, 3H), 5.97 (s, 1H), 3.75(t, J=5.8, 2H), 3.32-3.28 (m, 2H), 3.21 (t, J=5.8, 2H), 2.56-2.48 (m,1H), 2.16-2.10 (m, 1H), 1.74-1.60 (m, 2H).

Example 160(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.2; m/z found, 310.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.25 (m, 2H), 7.19-7.10 (m, 3H), 5.67 (s, 1H), 4.61(br s, 2H), 3.77-3.10 (br m, 5H), 2.46 (m, 4H), 2.19-2.10 (m, 1H),2.03-1.93 (m, 1H), 1.88-1.75 (m, 1H), 1.75-1.67 (m, 1H), 1.37-1.28 (m,1H).

Example 161 4-(3-Amino-azetidin-1-yl)-6-indan-2-yl-pyrimidin-2-ylaminesalt

MS (ESI): mass calcd. for C₁₆H₁₉N₅, 281.2; m/z found, 282.2 [M+H]⁺. ¹HNMR (MeOD): 7.26-7.20 (m, 2H), 7.20-7.15 (m, 2H), 6.00 (s, 1H),4.60-4.50 (m, 2H), 4.31-4.19 (m, 3H), 3.65-3.56 (m, 1H), 3.45-3.35 (m,2H), 3.19-3.13 (m, 2H).

Example 162(R)-4-(3-Amino-pyrrolidin-1-yl)-6-indan-2-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₁N₅, 295.2; m/z found, 296.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.24-7.20 (m, 2H), 7.18-7.14 (m, 2H), 6.00-5.70 (m, 1H),5.63 (s, 1H), 3.74-3.65 (m, 2H), 3.63-3.52 (m, 3H), 3.38-3.27 (m, 3H),3.20-3.10 (m, 3H), 2.19-2.09 (m, 1H), 1.83-1.70 (m, 1H).

Example 163 4-Indan-2-yl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.2; m/z found, 310.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.23-7.19 (m, 2H), 7.17-7.13 (m, 2H), 5.89 (s, 1H), 4.76(br s, 2H), 3.60-3.57 (m, 4H), 3.55-3.46 (m, 1H), 3.30-3.14 (m, 4H),2.45-2.42 (m, 4H), 2.32 (s, 3H).

Example 164(R)-4-Indan-2-yl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.2; m/z found, 310.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.23-7.19 (m, 2H), 7.17-7.13 (m, 2H), 5.67 (s, 1H), 4.72(br s, 2H), 3.71-3.36 (br m, 4H), 3.33-3.14 (m, 6H), 2.46 (s, 3H),2.20-2.08 (m, 1H), 1.88-1.78 (m, 1H).

Example 165 4-Indan-2-yl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₁N₅, 295.2; m/z found, 296.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.23-7.19 (m, 2H), 7.17-7.13 (m, 2H), 5.87 (s, 1H), 5.16(br s, 2H), 3.57-3.46 (m, 5H), 3.33-3.15 (m, 4H), 2.91-2.88 (m, 4H).

Example 166 4-(3-Amino-azetidin-1-yl)-6-benzyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₇N₅, 255.2; m/z found, 256.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.33-7.19 (m, 5H), 5.39 (s, 1H), 4.83 (br s, 2H), 4.25-4.18(m, 2H), 3.95-3.86 (m, 1H), 3.77 (s, 2H), 3.61-3.57 (m, 2H).

Example 167 (R)-4-(3-Amino-pyrrolidin-1-yl)-6-benzyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.2; m/z found, 270.12 [M+H]⁺. ¹HNMR (CDCl₃): 7.34-7.21 (m, 5H), 5.72 (br s, 2H), 5.45 (s, 1H), 3.83 (s,2H), 3.71-3.60 (m, 2H), 3.60-2.84 (br m, 5H), 2.21-2.04 (m, 1H),1.84-1.63 (m, 1H).

Example 168 N⁴-(2-Amino-ethyl)-6-indan-2-yl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.2; m/z found, 270.2 [M+H]⁺. ¹HNMR (MeOD): 8.49 (s, 2H), 7.26-7.20 (m, 2H), 5.94 (s, 1H), 3.67 (t,J=5.7, 2H), 3.59-3.51 (m, 1H), 3.39-3.32 (m, 2H), 3.18-3.06 (m, 4H).

Example 169(R)-4-(2,3-Dihydro-benzofuran-2-yl)-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₁N₅O, 311.2; m/z found, 312.2 [M+H]⁺.

Example 1704-(cis-Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅O, 303.2; m/z found, 304.2 [M+H]⁺.

Example 1714-(2,3-Dihydro-benzofuran-2-yl)-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₁₉N₅O, 297.2; m/z found, 298.2 [M+H]⁺.

Example 1724-(3-Amino-azetidin-1-yl)-6-(2,3-dihydro-benzofuran-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₇N₅O, 283.2; m/z found, 284.1 [M+H]⁺.

Example 1734-(cis-Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-indan-2-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₉H₂₃N₅, 321.2; m/z found, 322.2 [M+H]⁺.

Example 174(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(4-methyl-tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, 278.2 [M+H]⁺.

Example 175(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.17; m/z found, 264.2 [M+H]⁺. ¹HNMR (CD₃OD): 5.78 (s, 1H), 4.05-3.97 (m, 2H), 3.80-3.59 (br m, 3H),3.56-3.45 (m, 3H), 2.67-2.56 (m, 1H), 2.35-2.54 (m, 1H), 2.03-1.89 (m,1H), 1.81-1.70 (m, 4H).

Example 176N⁴-(2-Amino-ethyl)-6-(tetrahydro-pyran-4-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.2 [M+H]⁺.

Example 177N⁴-(2-Amino-ethyl)-N⁴-methyl-6-(tetrahydro-pyran-4-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2; m/z found, 252.2 [M+H]⁺.

Example 178(R)-4-(3-Amino-pyrrolidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.2; m/z found, 284.2[M+H]⁺=284.2. ¹H NMR (CDCl₃): 7.29-7.15 (m, 5H), 5.54 (s, 1H), 5.04 (brs, 2H), 3.75-3.05 (br m, 5H), 2.97 (dd, J=12.9, 6.3, 2H), 2.74 (app dd,J=9.5, 6.7, 2H), 2.13 (dt, J=12.8, 6.4, 2H), 1.80-1.51 (br m, 3H).

Example 179 4-(4-Methyl-piperazin-1-yl)-6-phenethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.2; m/z found, 298.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.15 (m, 5H), 5.75 (s, 1H), 4.81 (br s, 2H), 3.59-3.55(m, 4H), 2.96 (dd, J=9.6, 6.6, 2H), 2.74 (dd, J=9.5, 6.7, 2H), 2.44-2.40(m, 4H), 2.31 (s, 3H).

Example 180(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₃N₅, 297.20; m/z found, 298.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.15 (m, 5H), 5.55 (s, 1H), 4.93 (br s, 2H), 3.80-3.10(br m, 5H), 2.98-2.94 (m, 2H), 2.71-2.75 (m, 2H), 2.45 (s, 3H), 2.13(dt, J=12.9, 6.3, 1H), 1.84-1.74 (m, 1H).

Example 1814-(4-Methyl-piperazin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₈F₃N₅, 289.15; m/z found, 290.2 [M+H]⁺.¹H NMR (MeOD): 6.03 (s, 1H), 3.67-3.59 (m, 3H), 2.66 (dd, J=10.3, 6.2,2H), 2.57-2.43 (m, 6H), 2.31 (s, 3H).

Example 1824-Piperazin-1-yl-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₆F₃N₅, 275.14; m/z found, 276.2 [M+H]⁺.¹H NMR (MeOD): 6.04 (s, 1H), 3.67-3.62 (m, 4H), 2.95-2.87 (m, 4H), 2.67(dd, J=10.2, 6.2, 2H), 2.58-2.43 (m, 2H).

Example 183(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₈F₃N₅, 289.15; m/z found, 290.2 [M+H]⁺.¹H NMR (MeOD): 5.78 (s, 1H), 3.71-3.52 (m, 2H), 3.51-3.38 (m, 1H),3.38-3.22 (m, 2H), 2.65 (dd, J=10.3, 6.1, 2H), 2.57-2.44 (m, 2H), 2.41(s, 3H), 2.20 (dtd, J=13.2, 5.5, 1H), 1.94-1.80 (m, 1H).

Example 184(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(3,3,3-trifluoro-propyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₆F₃N₅, 275.14; m/z found, 276.2 [M+H]⁺.¹H NMR (MeOD): 5.78 (s, 1H), 3.71-3.55 (m, 3H), 3.53-3.41 (m, 1H),3.25-3.16 (m, 1H), 2.66 (dd, J=10.2, 6.2, 2H), 2.57-2.43 (m, 2H),2.25-2.14 (m, 1H), 1.90-1.78 (m, 1H).

Example 1854-Cyclopentyl-5-methoxy-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅O, 291.2; m/z found, 292.3 [M+H]⁺. ¹HNMR (MeOD): 3.8-3.7 (m, 4H), 3.6 (s, 3H), 3.5-3.4 (m, 1H), 2.6-2.6 (m,4H), 2.4 (s, 3H), 1.9-1.8 (m, 4H), 1.8-1.6 (m, 4H)

Example 186 4-Cyclopentyl-5-methoxy-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.1; m/z found, 278.3 [M+H]⁺. ¹HNMR (MeOD): 3.7-3.6 (m, 4H), 3.6 (s, 3H), 3.5-3.4 (m, 1H), 3.0-2.8 (m,4H), 1.9-1.6 (m, 8H).

Example 187(R)-4-Cyclopentyl-5-methoxy-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₅N₅O, 291.2; m/z found, 292.2 [M+H]⁺. ¹HNMR (MeOD): 3.83 (dd, J=11.7, 6.3, 1H), 3.80-3.74 (m, 1H), 3.70-3.62 (m,1H), 3.54 (s, 3H), 3.48 (dd, J=11.6, 5.4, 1H), 3.43-3.34 (m, 1H),3.30-3.22 (m, 1H), 2.41 (s, 3H), 2.20-2.10 (m, 1H), 1.93-1.62 (m, 9H).

Example 188(R,R)-4-Cyclopentyl-5-methoxy-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₇N₅O, 317.2; m/z found, 318.2 [M+H]⁺. ¹HNMR (MeOD): 4.34-4.17 (m, 1H), 4.12-3.82 (m, 3H), 3.75-3.68 (m, 3H),3.56-3.45 (m, 1H), 3.42-3.34 (m, 1H), 3.11-3.02 (m, 1H), 2.91-2.73 (m,1H), 2.18-2.03 (m, 2H), 2.02-1.59 (m, 11H).

Example 189N⁴-(2-Amino-ethyl)-N⁴-methyl-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.71 (s, 1H), 4.98 (s, 2H), 4.19-3.93 (m, 2H), 3.90-3.80(m, 2H), 3.65-3.51 (m, 1H), 3.44 (s, 3H), 3.31-3.07 (m, 1H), 2.88-2.84(m, 2H), 2.49 (s, 3H), 2.30-2.04 (m, 2H).

Example 1904-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₃N₅O, 289.2; m/z found, 290.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.66 (s, 1H), 5.25 (s, 2H), 4.11-3.96 (m, 2H), 3.90-3.81(m, 2H), 3.72-3.28 (m, 5H), 3.28-3.15 (m, 1H), 3.03-2.93 (m, 1H),2.70-2.59 (m, 1H), 2.47-2.18 (m, 3H), 2.18-2.04 (m, 1H), 1.86-1.68 (m,2H), 1.66-1.57 (m, 1H), 1.54-1.43 (m, 1H).

Example 191(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.2; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.64 (s, 1H), 5.23 (s, 2H), 4.15-3.94 (m, 2H), 3.90-3.80(m, 2H), 3.70-3.14 (m, 6H), 2.46 (s, 3H), 2.30-2.06 (m, 3H), 1.94-1.43(m, 2H).

Example 1924-[1,4]Diazepan-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.2; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.77 (s, 1H), 5.10 (s, 2H), 4.09-3.97 (m, 2H), 3.88-3.82(m, 2H), 3.72-3.59 (m, 4H), 3.24-3.16 (m, 1H), 2.99-2.94 (m, 2H),2.88-2.79 (m, 2H), 2.32-2.05 (m, 2H), 2.04-1.88 (m, 1H), 1.89-1.78 (m,2H).

The compounds in Examples 193-194 were obtained by chiral HPLCseparation of the enantiomers of Example 56 (column, ADH; eluent, 95%(hexanes/0.2% TEA)/5% [(1:1 MeOH/EtOH)/0.2% TEA].

Example 193(−)-4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

[α]²⁵ _(D) −9.0° (c 1.00, CH₃OH). MS (ESI): mass calcd. for C₁₂H₁₉N₅O,249.2; m/z found, 250.2 [M+H]⁺. ¹H NMR (CDCl₃): 5.86 (s, 1H), 5.80-4.99(m, 3H), 4.06-3.97 (m, 2H), 3.90-3.80 (m, 2H), 3.69-3.54 (m, 4H),3.30-3.18 (m, 1H), 3.02-2.87 (m, 4H), 2.33-2.21 (m, 1H), 2.17-2.05 (m,1H).

Example 194(+)-4-Piperazin-1-yl-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine

[α]²⁵ _(D) +8.6° (c 1.00, CH₃OH). MS (ESI): mass calcd. for C₁₂H₁₉N₅O,249.2; m/z found, 250.2 [M+H]⁺. ¹H NMR (CDCl₃): 5.86 (s, 1H), 5.80-4.99(m, 3H), 4.06-3.97 (m, 2H), 3.90-3.80 (m, 2H), 3.69-3.54 (m, 4H),3.30-3.18 (m, 1H), 3.02-2.87 (m, 4H), 2.33-2.21 (m, 1H), 2.17-2.05 (m,1H).

Example 195N⁴-(2-Amino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.1; m/z found, 224.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.95 (br s, 1H), 5.67 (s, 1H), 5.37 (s, 2H), 4.06-3.96 (m,2H), 3.89-3.79 (m, 2H), 3.33 (s, 2H), 3.23-3.13 (m, 1H), 2.89 (t, J=5.8,2H), 2.28-2.16 (m, 1H), 2.15-2.05 (m, 1H), 1.81 (br s, 2H).

Example 196N⁴-(3-Amino-propyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.83 (s, 1H), 4.68-4.42 (m, 5H), 4.07-3.95 (m, 2H),3.88-3.76 (m, 2H), 3.47 (t, J=5.9, 2H), 3.26-3.16 (m, 1H), 2.94 (t,J=6.5, 2H), 2.35-2.22 (m, 1H), 2.13-1.99 (m, 1H), 1.99-1.86 (m, 2H).

Example 197N⁴-Methyl-N⁴-(2-methylamino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.2; m/z found, 252.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.79 (s, 1H), 5.36 (br s, 2H), 4.08-3.96 (m, 2H), 3.89-3.80(m, 2H), 3.62 (t, J=6.3, 2H), 3.25-3.15 (m, 1H), 3.01 (s, 3H), 2.78 (t,J=6.5, 2H), 2.45 (s, 3H), 2.28-2.08 (m, 2H), 1.57 (s, 1H).

Example 198N⁴-(2-Methylamino-ethyl)-6-(tetrahydro-furan-3-yl)-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.79 (s, 1H), 5.21 (s, 2H), 4.09-3.97 (m, 2H), 3.89-3.82(m, 2H), 3.56 (t, J=6.5, 2H), 3.26-3.15 (m, 1H), 3.02 (s, 3H), 2.89 (t,J=6.6, 2H), 2.28-2.08 (m, 2H), 1.44 (br s, 2H).

Example 1995-Fluoro-4-methyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₆FN₅, 225.1; m/z found, 226.2 [M+H]⁺. ¹HNMR (CDCl₃): 4.76 (s, 2H), 3.72-3.68 (m, 4H), 2.48-2.44 (m, 4H), 2.31(s, 3H), 2.21 (d, J=3.5, 3H).

Example 2005-Fluoro-4-methyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₁₈FN₅, 251.2; m/z found, 252.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.05 (s, 2H), 3.78-3.56 (m, 5H), 3.40-3.34 (m, 1H),3.06-2.97 (m, 1H), 2.70-2.61 (m, 1H), 2.34-2.24 (m, 1H), 2.17 (d, J=3.4,3H), 1.81-1.43 (m, 4H).

Example 201 5-Fluoro-4-methyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₉H₁₄FN₅, 211.1; m/z found, 212.1 [M+H]⁺. ¹HNMR (CDCl₃): 4.03-3.94 (m, 3H), 3.75-3.61 (m, 4H), 3.04-2.79 (m, 4H),2.27-2.11 (m, 3H).

Example 202(R)-5-Fluoro-4-methyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₆FN₅, 225.1; m/z found, 226.1 [M+H]⁺. ¹HNMR (CDCl₃): 5.37 (s, 2H), 3.78-3.67 (m, 2H), 3.65-3.56 (m, 1H),3.47-3.38 (m, 1H), 3.28-3.20 (m, 1H), 2.43 (s, 3H), 2.15 (d, J=3.3, 3H),2.10-1.99 (m, 1H), 1.84-1.71 (m, 1H), 1.48 (s, 1H).

Example 203N⁴-(2-Amino-ethyl)-5-fluoro-6,N⁴-dimethyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₈H₁₄FN₅, 199.1; m/z found, 200.1 [M+H]⁺. ¹HNMR (CDCl₃): 4.92 (s, 2H), 3.56 (t, J=6.3, 2H), 3.13 (d, J=2.9, 3H),2.92 (t, J=6.6, 2H), 2.19 (d, J=3.6, 3H), 1.41 (br s, 2H).

Example 204 4-Piperazin-1-yl-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₈N₆, 270.2; m/z found, 271.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.44 (dd, J=4.5, 1.6, 2H), 7.29 (d, J=6.1, 2H), 5.89 (s,1H), 4.71 (br s, 3H), 3.79 (s, 2H), 3.60-3.56 (m, 4H), 2.90-2.85 (m,4H).

Example 205(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.2; m/z found, 285.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.49 (dd, J=4.5, 1.6, 2H), 7.18 (d, J=6.0, 2H), 5.52 (s,1H), 5.26 (s, 2H), 3.73 (s, 2H), 3.67-3.37 (m, 3H), 3.37-3.23 (m, 2H),2.43 (s, 3H), 2.17-2.04 (m, 1H), 1.80 (br s, 2H).

Example 2064-(4-Methyl-piperazin-1-yl)-6-pyridin-4-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₂₀N₆, 284.2; m/z found, 285.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.51 (dd, J=4.4, 1.6, 2H), 7.20-7.17 (m, 2H), 5.74 (s, 1H),4.96 (s, 2H), 3.75 (s, 2H), 3.59-3.53 (m, 4H), 2.44-2.39 (m, 4H), 2.31(s, 3H).

Example 2074-(4-Methyl-piperazin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₉N₅S, 289.1; m/z found, 290.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.24 (dd, J=4.9, 3.0, 1H), 7.05-7.03 (m, 1H), 6.98 (dd,J=4.9, 1.2, 1H), 5.74 (s, 1H), 5.07 (s, 2H), 3.78 (s, 2H), 3.57-3.51 (m,4H), 2.42-2.37 (m, 4H), 2.29 (s, 3H).

Example 208(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₉N₅S, 289.1; m/z found, 290.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.21 (dd, J=4.9, 3.0, 1H), 7.03-7.00 (m, 1H), 6.96 (dd,J=4.9, 1.2, 1H), 5.50 (s, 1H), 5.47 (s, 2H), 3.74 (s, 2H), 3.63-3.32 (m,4H), 3.29-3.15 (m, 2H), 2.40 (s, 3H), 2.09-2.00 (m, 1H), 1.80-1.67 (m,1H).

Example 209 4-Piperazin-1-yl-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₇N₅S, 275.1; m/z found, 276.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.30-7.26 (m, 1H), 7.10-7.04 (m, 1H), 6.97 (d, J=4.5, 1H),5.78 (s, 1H), 4.44-4.29 (m, 3H), 3.77 (s, 2H), 3.57-3.49 (m, 4H),2.94-2.80 (m, 4H).

Example 210(R)-4-(3-Amino-pyrrolidin-1-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₇N₅S, 275.1; m/z found, 276.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.26-7.21 (m, 1H), 7.04 (s, 1H), 6.98 (d, J=4.6, 1H), 5.52(s, 1H), 5.16 (s, 2H), 3.77 (s, 2H), 3.65-3.57 (m, 2H), 3.53-2.85 (m,3H), 2.19-1.95 (m, 1H), 1.76-1.65 (m, 1H), 1.63-1.42 (m, 2H).

Example 2114-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-thiophen-3-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅S, 315.2; m/z found, 316.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.24 (dd, J=4.9, 3.0, 1H), 7.07-7.03 (m, 1H), 6.98 (d,J=4.7, 1H), 5.58-5.47 (m, 1H), 5.13 (s, 2H), 3.77 (s, 2H), 3.67-3.06 (m,6H), 3.01-2.88 (m, 1H), 2.66-2.58 (m, 1H), 2.35-2.15 (m, 1H), 1.74-1.52(m, 3H), 1.50-1.41 (m, 1H).

Example 212N⁴-(2-Amino-ethyl)-6-thiophen-3-ylmethyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₅N₅S, 249.1; m/z found, 250.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.23 (dd, J=4.9, 3.0, 1H), 7.04-7.01 (m, 1H), 6.95 (dd,J=4.9, 1.15, 1H), 5.94-5.67 (m, 1H), 5.52 (s, 1H), 5.33 (s, 2H), 3.74(s, 2H), 3.33-3.20 (m, 2H), 2.81 (t, J=5.8, 2H), 1.72-1.58 (m, 2H).

Example 2134-(4-Methyl-piperazin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₉N₅S, 289.1; m/z found, 290.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.13 (dd, J=5.1, 1.2, 1H), 6.90 (dd, J=5.1, 3.4, 1H),6.88-6.85 (m, 1H), 5.79 (s, 1H), 5.41 (s, 2H), 3.93 (s, 2H), 3.55-3.50(m, 4H), 2.38-2.34 (m, 4H), 2.26 (s, 3H).

Example 214(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₁₉N₅S, 289.1; m/z found, 290.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.11 (dd, J=5.1, 1.2, 1H), 6.89 (dd, J=5.1, 3.4, 1H),6.87-6.85 (m, 1H), 5.56 (s, 1H), 5.54 (s, 2H), 3.91 (s, 2H), 3.74-2.64(m, 6H), 2.38 (s, 3H), 2.08-1.98 (m, 1H), 1.78-1.66 (m, 1H).

Example 215 4-Piperazin-1-yl-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₇N₅S, 275.1; m/z found, 276.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.18 (dd, J=5.1, 1.2, 1H), 6.94 (dd, J=5.1, 3.4, 1H),6.91-6.89 (m, 1H), 5.85 (s, 1H), 4.57 (s, 3H), 3.94 (s, 2H), 3.55-3.51(m, 4H), 2.86-2.82 (m, 4H).

Example 216(R)-4-(3-Amino-pyrrolidin-1-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₁₇N₅S, 275.1; m/z found, 276.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.13 (dd, J=5.1, 1.2, 1H), 6.91 (dd, J=5.1, 3.4, 1H),6.88-6.86 (m, 1H), 5.57 (s, 1H), 5.39 (s, 2H), 3.93 (s, 2H), 3.85-3.01(m, 6H), 2.15-1.99 (m, 1H), 1.79-1.23 (m, 2H).

Example 2174-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-thiophen-2-ylmethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅S, 315.2; m/z found, 316.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.14 (dd, J=5.1, 1.1, 1H), 6.92 (dd, J=5.0, 3.5, 1H),6.89-6.87 (m, 1H), 5.64-5.54 (m, 1H), 5.10 (s, 2H), 3.94 (s, 2H),3.66-3.08 (m, 5H), 3.02-2.90 (m, 1H), 2.67-2.56 (m, 1H), 2.34-2.15 (m,1H), 1.77-1.51 (m, 4H), 1.49-1.40 (m, 1H).

Example 218N⁴-(2-Amino-ethyl)-6-thiophen-2-ylmethyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₁H₁₅N₅S, 249.1; m/z found, 250.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.19 (dd, J=5.1, 1.1, 1H), 6.93 (dd, J=5.1, 3.5, 1H),6.90-6.88 (m, 1H), 5.71 (s, 1H), 4.76 (s, 5H), 3.89 (s, 2H), 3.41-3.31(m, 2H), 2.81 (t, J=6.0, 2H).

Example 219 N⁴-(2-Amino-ethyl)-6-methoxymethyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₈H₁₅N₅O, 197.1; m/z found, 198.1 [M+H]⁺.

Example 2204-(3-Amino-azetidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₉H₁₅N₅O, 209.1; m/z found, 210.1 [M+H]⁺. ¹HNMR (MeOD): 5.77 (s, 1H), 4.25 (t, J=8.2, 2H), 4.18-4.15 (m, 2H),3.95-3.85 (m, 1H), 3.76-3.68 (m, 2H), 3.41 (s, 3H).

Example 221(R)-4-Methoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.1 [M+H]⁺. ¹HNMR (MeOD): 5.92 (s, 1H), 4.23-4.15 (m, 2H), 3.84-3.44 (m, 3H), 3.42 (s,3H), 3.38-3.25 (m, 2H), 2.40 (s, 3H), 2.28-2.13 (m, 1H), 1.96-1.78 (m,1H).

Example 222(R)-4-(3-Amino-pyrrolidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.1; m/z found, 224.1 [M+H]⁺. ¹HNMR (MeOD): 6.10 (s, 1H), 4.31 (s, 2H), 3.99 (s, 1H), 3.91-3.81 (m, 1H),3.80-3.57 (m, 3H), 3.45 (s, 3H), 2.53-2.35 (m, 1H), 2.21-2.09 (m, 1H).

Example 2234-Methoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.1 [M+H]⁺. ¹HNMR (MeOD): 6.15 (s, 1H), 4.19-4.18 (m, 2H), 3.67-3.62 (m, 4H), 3.41 (s,3H), 2.51-2.41 (m, 4H), 2.31 (s, 3H).

Example 224 4-Methoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₇N₅O, 223.1; m/z found, 224.1 [M+H]⁺. ¹HNMR (MeOD): 6.13 (s, 1H), 4.19 (s, 2H), 3.64-3.55 (m, 4H), 3.41 (s, 3H),2.89-2.79 (m, 4H).

Example 225(R)-4-(3-Amino-piperidin-1-yl)-6-methoxymethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.2; m/z found, 238.1 [M+H]⁺. ¹HNMR (MeOD): 6.17 (s, 1H), 4.31-4.24 (m, 1H), 4.18 (s, 2H), 4.15-4.07 (m,1H), 3.42 (s, 3H), 3.06-2.97 (m, 1H), 2.90-2.76 (m, 2H), 2.06-1.95 (m,1H), 1.82-1.71 (m, 1H), 1.58-1.36 (m, 2H).

Example 226(R,R)-4-Methoxymethyl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.2; m/z found, 264.1 [M+H]⁺. ¹HNMR (MeOD): 5.94 (s, 1H), 4.19 (s, 2H), 3.72-3.47 (m, 3H), 3.42 (s, 4H),3.01-2.89 (m, 1H), 2.72-2.61 (m, 2H), 2.54-2.32 (m, 1H), 1.88-1.73 (m,2H), 1.72-1.58 (m, 1H), 1.56-1.46 (m, 1H).

Example 2274-(4-Methyl-piperazin-1-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, 278.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.90 (s, 1H), 4.75 (br s, 2H), 4.21 (app p, J=6.4, 1H),3.90 (dd, J=14.6, 7.2, 1H), 3.74 (dd, J=14.2, 7.9, 1H), 3.60 (t, J=5.0,4H), 2.64 (dq, J=13.6, 6.4, 2H), 2.42 (t, J=5.1, 4H), 2.3 (s, 3H),2.05-1.98 (m, 1H), 1.92-1.80 (m, 2H), 1.63-1.52 (m, 1H).

Example 228(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₃N₅O, 277.2; m/z found, 278.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.70 (s, 1H), 4.75 (br s, 2H), 4.20 (app p, J=6.4, 1H),3.88 (dd, J=14.6, 7.2, 1H), 3.72 (dd, J=14.2, 7.9, 1H), 3.70-3.20 (m,5H), 2.64 (ddd, J=19.0, 13.5, 6.5, 2H), 2.42 (s, 3H), 2.18-2.08 (m, 1H),2.05-1.80 (m, 5H), 1.63-1.52 (m, 1H).

Example 2294-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅O, 303.2; m/z found, 304.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.70 (s, 1H), 4.80 (br s, 2H), 4.20 (app p, J=6.4, 1H),3.90 (dd, J=14.2, 7.7, 1H), 3.72 (dd, J=14.2, 7.9, 1H), 3.65-3.55 (m,2H), 3.40-3.30 (m, 2H), 2.98-2.90 (m, 2H), 2.72-2.55 (m, 3H), 2.42-2.40(m, 3H), 2.32 (s, 3H), 2.05-1.80 (m, 3H), 1.63-1.52 (m, 1H).

Example 2304-Piperazin-1-yl-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.2; m/z found, 264.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.90 (s, 1H), 4.72 (br s, 2H), 4.22 (app p, J=6.4, 1H),3.90 (dd, J=14.6, 7.2, 1H), 3.73 (dd, J=14.2, 7.9, 1H), 3.55 (t, J=5.1,4H), 2.90 (t, J=5.1, 4H), 2.63 (dq, J=13.6, 6.4, 2H), 2.05-1.80 (m, 3H),1.63-1.55 (m, 1H).

Example 2314-(cis-Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6-(tetrahydro-furan-2-ylmethyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₅N₅O, 303.2; m/z found, 304.2 [M+H]⁺. ¹HNMR (CDCl₃): 5.70 (br s, 1H), 4.75 (br s, 2H), 4.22 (app p, J=6.4, 1H),3.90 (dd, J=14.6, 7.2, 1H), 3.73 (dd, J=14.2, 7.9, 1H), 3.55-3.30 (m,5H), 2.99 (td, J=11.8, 3.4, 1H), 2.70-2.58 (m, 3H), 2.40-2.20 (m, 1H),2.05-1.40 (m, 8H).

Example 2324-(4-Chloro-benzyl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₀ClN₅, 317.1; m/z found, 318.1 [M+H]⁺. ¹HNMR (CDCl₃): 7.29-7.23 (m, 2H), 7.21-7.16 (m, 2H), 5.70 (s, 1H), 3.74(s, 2H), 3.57-3.52 (m, 4H), 2.43-2.39 (m, 4H), 2.31 (s, 3H), 1.92-1.85(m, 2H)

Example 233 4-(4-Chloro-benzyl)-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₈ClN₅, 303.13; m/z found, 304.1 [M+H]⁺.¹H NMR (MeOD): 7.42-7.36 (m, 2H), 7.35-7.30 (m, 2H), 6.49 (s, 1H), 4.22(s, 2H), 3.55-3.52 (m, 4H), 3.39-3.33 (m, 4H)

Example 234(R)-4-(4-Chloro-benzyl)-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₀ClN₅, 317.1; m/z found, 318.1 [M+H]⁺. ¹HNMR (MeOD): 7.30-7.19 (m, 4H), 5.70 (s, 1H), 3.72 (s, 2H), 3.69-3.32 (m,5H), 2.42 (s, 3H), 2.26-2.13 (m, 1H), 1.93-1.80 (m, 1H).

Example 235(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(4-chloro-benzyl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₈ClN₅, 303.79; m/z found, 304.1 [M+H]⁺.

Example 2364-(4-Chloro-benzyl)-6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₈H₂₂ClN₅, 343.14; m/z found, 344.1 [M+H]⁺.

Example 2374-(4-Chloro-benzyl)-6-(cis-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₇H₂₀ClN₅, 329.14; m/z found, 330.1 [M+H]⁺.

Example 238N⁴-(2-Amino-ethyl)-6-(4-chloro-benzyl)-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₄H₁₈ClN₅, 291.13; m/z found, 292.1 [M+H]⁺.

Example 2394-Ethyoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.3; m/z found, 252.2 [M+H]⁺. ¹HNMR (MeOD): 6.53 (s, 1H), 4.47 (s, 2H), 4.46-3.70 (m, 4H), 3.64 (q,J=7.0, 2H), 3.47-3.40 (m, 4H), 2.96 (s, 3H), 1.28 (t, J=7.0, 3H).

Example 240 4-Ethoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.3; m/z found, 238.2 [M+H]⁺. ¹HNMR (MeOD): 6.54 (s, 1H), 4.48 (s, 2H), 4.40-3.91 (m, 4H), 3.64 (q,J=7.0, 2H), 3.60 (m, 4H), 1.27 (t, J=7.0, 3H).

Example 241(R)-Ethoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.3; m/z found, 252.2 [M+H]⁺. ¹HNMR (MeOD): 6.22 (s, 1H), 4.46 (s, 2H), 4.03-3.88 (m, 3H), 3.82 (m, 1H),3.74 (m, 0.5H), 3.64 (m, 2H), 3.58-3.39 (m, 0.5H), 2.79 (m, 3H),2.61-2.19 (m, 2H), 1.28 (t, J=7.0, 3H).

Example 242(R)-Ethoxymethyl-6-(3-amino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₉N₅O, 237.3; m/z found, 238.2 [M+H]⁺. ¹HNMR (MeOD): 6.27 (m, 1H), 4.49 (s, 2H), 4.10 (m, 1H), 3.98 (m, 1H),3.93-3.70 (m, 3H), 3.66 (s, 1H), 3.65 (q, J=7.0, 2H), 2.55 (m, 1H), 2.28(m, 1H), 1.28 (t, J=7.0, 3H).

Example 243Isopropoxymethyl-6-((R)-3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.4; m/z found, 266.3 [M+H]⁺. ¹HNMR (MeOD): 6.27 (m, 1H), 4.50 (s, 2H), 4.00 (m, 3H), 3.79 (m, 3H), 3.66(s, 2H), 2.79 (m, 3H), 2.63-2.22 (m, 2H), 1.25 (m, 6H).

Example 244 4-Isopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.3; m/z found, 252.2 [M+H]⁺. ¹HNMR (MeOD): 5.94 (s, 1H), 4.23 (s, 2H), 3.68 (quintet, J=6.1, 1H), 3.62(m, 4H), 3.56-3.32 (m, 1H), 3.25-2.90 (m, 1H), 2.50-2.15 (m, 1H),1.91-1.75 (m, 1H), 1.21 (m, 6H).

Example 245(R)-Isopropoxymethyl-6-(3-amino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₂H₂₁N₅O, 251.3; m/z found, 252.2 [M+H]⁺. ¹HNMR (MeOD): 6.16 (s, 1H), 4.24 (s, 2H), 3.68 (quintet, J=6.1, 1H),3.66-3.58 (m, 4H), 3.49-3.38 (m, 1H), 2.82 (m, 4H), 1.23 (m, 6H).

Example 2464-Isopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

To a solution of 2-amino-6-isopropoxymethyl-3H-pyrimidin-4-one (0.050 g,0.27 mmol) in acetonitrile (2.37 mL) was addedbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.157 g, 0.355 mmol), DBU (0.82 mL, 0.55 mmol), and 1-methyl-piperazine(0.091 ml, 0.82 mmol). The reaction mixture was stirred at rt for 12 h,then at 60° C. for 3 h. The mixture was concentrated and the resultantresidue was purified (2 M NH₃ in MeOH/CH₂Cl₂) to yield a white solid (10mg, 14%). MS (ESI): mass calcd. for C₁₃H₂₃N₅O, 265.4; m/z found, 266.3[M+H]⁺. ¹H NMR (MeOD): 6.55 (s, 1H), 4.49 (s, 2H), 3.78 (quintet, J=6.1,1H), 3.70-3.00 (m, 8H), 2.95 (s, 3H), 1.25 (d, J=6.1, 6H).

Example 247 4-Phenethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₆H₂₁N₅, 283.18; m/z found, 284.2 [M+H]⁺.

Example 248 4-(3-Amino-azetidin-1-yl)-6-phenethyl-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₅H₁₉N₅, 269.16; found, 270.2 [M+H]⁺.

Example 249(R)-4-(3-Amino-pyrrolidin-1-yl)-6-(tetrahydro-pyran-4-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₃H₂₁N₅O, 263.17; found, 264.2 [M+H]⁺.

Example 250 N⁴-(2-Amino-ethyl)-6-benzyl-N⁴-methyl-pyrimidine-2,4-diamine

MS (ESI): mass calcd. for C₁₄H₁₉N₅, 257.1; found, 258.2 [M+H]⁺.

Example 2514-Indan-2-yl-6-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₂₀H₂₅N₅, 335.21; found, 336.2 [M+H]⁺.

Example 2524-(3-Amino-azetidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₀H₁₅N₅O, 221.1; m/z found, 222.2 [M+H]⁺.

Example 2534-(3-Amino-azetidin-1-yl)-5,6,7,8-tetrahydro-quinazolin-2-ylamine

MS (ESI): mass calcd. for C₁₁H₁₇N₅, 219.2; m/z found, 220.2 [M+H]⁺.

Example 2544-(cis-5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-ylamine

MS (ESI): mass calcd. for C₁₄H₂₁N₅O, 275.2; m/z found, 276.3 [M+H].

The compounds in Examples 255-256 were obtained by preparativesupercritical fluid chromatography (SFC) of Example 160 by preparativeHPLC using a Kromasil Cellucoat 5 micron 250×21.2 (L×I.D.) column, amobile phase of 15% MeOH with 0.2% isopropylamine and 85% CO₂, a flowrate of 40 mL/min, and a back pressure of 150 bar.

Example 255(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine(diastereomer 1)

SFC: R_(t)=19.9 min. MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.20; found,310.2 [M+H]⁺.

Example 256(R)-4-(3-Methylamino-pyrrolidin-1-yl)-6-(trans-2-phenyl-cyclopropyl)-pyrimidin-2-ylamine(diastereomer 2)

SFC: R_(t)=23.0 min. MS (ESI): mass calcd. for C₁₈H₂₃N₅, 309.20; found,310.2 [M+H]⁺.

The compounds in Examples 257-258 were obtained by preparativesupercritical fluid chromatography of Example 84 using a Chiralpak AD-H250×21 mm (L×I.D.) column at 25° C., a mobile phase of 6.25 mL/min MeOHwith 0.2% TEA and 25 g/min CO₂, a back pressure of 150 bar, and UVdetection at 214 nm.

Example 2574-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine(enantiomer 1)

HPLC: R_(t)=8.9 min.

Example 2584-Cyclopentyl-6-(cis-1,7-diaza-spiro[4.4]non-7-yl)-pyrimidin-2-ylamine(enantiomer 2)

HPLC: R_(t)=14.8 min.

The compounds in Examples 259-280 may be prepared using methodsanalogous to those described for the preceding examples.

Example 259(R)-4-Isopropoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

Example 260(R)-4-(3-Amino-pyrrolidin-1-yl)-6-isopropoxymethyl-pyrimidin-2-ylamine

Example 261 4-Isopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

Example 2624-Isopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

Example 2634-(3-Amino-azetidin-1-yl)-6-isopropoxymethyl-pyrimidin-2-ylamine

Example 2644-Isopropoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 265(R)-4-Cyclopropoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

Example 266(R)-4-(3-Amino-pyrrolidin-1-yl)-6-cyclopropoxymethyl-pyrimidin-2-ylamine

Example 267 4-Cyclopropoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

Example 2684-Cyclopropoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

Example 2694-(3-Amino-azetidin-1-yl)-6-cyclopropoxymethyl-pyrimidin-2-ylamine

Example 2704-Cyclopropoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 271(R)-4-tert-Butoxymethyl-6-(3-methylamino-pyrrolidin-1-yl)-pyrimidin-2-ylamine

Example 272(R)-4-(3-Amino-pyrrolidin-1-yl)-6-tert-butoxymethyl-pyrimidin-2-ylamine

Example 273 4-tert-Butoxymethyl-6-piperazin-1-yl-pyrimidin-2-ylamine

Example 2744-tert-Butoxymethyl-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamine

Example 2754-(3-Amino-azetidin-1-yl)-6-tert-butoxymethyl-pyrimidin-2-ylamine

Example 2764-tert-Butoxymethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 2774-Ethyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 2784-(8-Methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-6-propyl-pyrimidin-2-ylamine

Example 2794-Isopropyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 2804-Cyclopentyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-ylamine

Example 281 Crystal Forms

Bis hydrochloride salts of compounds of Formula (I) were dissolved inmethanol (40 mg/mL concentration) and aliquots (125 μL) were dispensedinto 96-well plates. The aliquots were evaporated to leave a 5 mg sampleof compound in each well. An aliquot (400 μL) of a polar or a non-polarsolvent, neat or as a mixture (1:1 or 2.25:1), were added to each well.Plates were covered, sonicated, and heated to 40° C. for 15 min.Solvents were allowed to evaporate. Residual solids were analyzed forcrystallinity. Crystalline forms were obtained from polar solvents,including methanol, ethanol, propanol, isopropanol, butanol, ethylacetate, propyl acetate, butyl acetate, acetone, and 2-butanone, andaqueous mixtures thereof, and from mixtures of polar solvents, includingmixtures of methanol, ethanol, propanol, isopropanol, butanol,2-butanol, methyl acetate, ethyl acetate, propyl acetate, butyl acetate,acetone, and 2-butanone. Crystalline forms were obtained from non-polarsolvents, including heptane, methyl ethyl ketone, chlorobenzene,chloroform, dichloromethane, isobutyl acetate, and toluene, and frommixtures of non-polar solvents, including mixtures of methyl tert-butylether, isobutyl acetate, toluene, dichlorobenzene, hexane, cyclohexane,heptane, methyl ethyl ketone, acetonitrile, pentane, THF, chloroform,and chlorobenzene.

Binding Assay on Recombinant Human Histamine H₄ Receptor.

Cell pellets from SK—N-MC cells stably or transiently transfected withhuman H₄ receptor were used for the binding assays. Cell pellets werehomogenized in 50 mM Tris/5 mM EDTA buffer and supernatants from an 800g spin were collected and recentrifuged at 30,000 g for 30 min. Pelletswere rehomogenized in 50 mM Tris/5 mM EDTA buffer. For competitionbinding studies, cell membranes were incubated with 2×K_(D) (10 nM),[³H] histamine (Specific activity: 23 C_(i)/mmol), with or without testcompounds for 45 min at 25° C. Compounds were tested in free base,hydrochloride salt, or trifluoroacetic acid form. Nonspecific bindingwas defined with 100 μM cold histamine. K_(i) values were calculatedbased on an experimentally determined appropriate K_(D) values accordingto Cheng and Prusoff (Biochem. Pharmacol. 1973, 22(23):3099-3108).Membranes were harvested by rapid filtration using the 96 well Brandelsystem or a cell harvester using a Whatman GF/C filter or filter platestreated with 0.5% polyethylenimine (PEI), and washed 4 times withice-cold 50 mM Tris/5 mM EDTA buffer. Filters were then dried, mixedwith scintillant and radioactive counts were determined. Results for thecompounds tested in theses assays are presented in Tables 1 and 2 as anaverage of results obtained (NT=not tested). Data marked with anasterisk (*) were obtained by the cell harvester method. Where activityis shown as greater than (>) a particular value, the value is thehighest concentration tested.

TABLE 1 Ex. K_(i) (nM) 1 1 2 1 3 257 4 1 5 30 6 6 7 2 8 3 9 820 10 15911 12 12 18 13 631 14 673 15 692 16 65 17 59 18 17 19 8 20 18 21 29 2218 23 77 24 49 25 286 26 177 27 >10000 28 357 29 >10000 30 530 31 24932 >10000 33 10 34 6 35 21 36 21 37 27 38 559 39 10 40 8 41 28 42 18 432 44 1 45 103 46 2 47 11 48 328 49 50 50 3 51 3 52 3 53 3 54 2 55 1 5620 57 27 58 41 59 29 60 31 61 24 62 30 63 21 64 36 65 47 66 4 67 17 68115 69 43 70 404 71 5 72 14 73 >10000 74 76 75 159

TABLE 2 Ex. K_(i) (nM) 80  1 81  2 82 25 83  3 84 11 85  6 86 56 87 328 88 520  89 19 90 14 91 84 92 281  93 481  94 497  95  8* 96 35 97 20 98298  99 214  100 262  101 30 102 181  103  22* 104  96* 105 103  106 39* 107 104  108 84 109 517* 110 80 111 33 112 46 113 136  114 71 1151431*  116 64 117 42 118 242  119 153  120 113  121  3 122 22 123  4124 >10000   125  7 126 23 127  9 128 19 129 46 130  8 131 412* 132 356*133 238* 134 130  135  4 136  1 137  2 138 44 139 138  140 397  141 84142  3 143 13 144  6 145 117  146  3 147  4 148  1 149  3 150 85 151  2152  6 153 97 154 49 155 82 156 12 157 29 158  8 159 42 160  3 161 24162  5 163  2 164  4 165  2 166 52 167 78 168 46 169 396  170 5891  171106  172 932  173 2071  174 138  175 85 176 335  177 1030  178  9 179  6180  8 181  8 182 20 183 16 184 13 185 300  186 213  187 10 188 18 189 6 190 11 191 12 192 17 193 31 194 49 195 59 196 203  197 204  198 2450 199 69 200 235  201 391  202 515  203 4230  204 45 205 230  206 81 207 2 208  8 209  2 210 12 211  4 212 12 213  4 214 19 215  6 216 32 217  9218 20 219 890  220 NT 221 43 222 23 223 15 224 26 225 464  226 14 22717 228 91 229 360  230 25 231 59 232  8 233 12 234 18 235 140  236 249 237 257  238 1769  239 29 240 25 241 31 242 22 243 NT 244 NT 245 NT 24632 247  3 248  9 249 87 250 564* 251  20* 252 >10000   253 >10000  254 >10000   255 34 256  5 257 31 258 34

While the invention has been illustrated by reference to examples, it isunderstood that the invention is intended not to be limited to theforegoing detailed description.

1. A method of making a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein R¹ is: a) a C₁₋₆alkyl group, optionally substituted with —OH,—OC₁₋₄alkyl, —CF₃, or —O— (monocyclic cycloalkyl); b) a benzyl,—CH₂-(monocyclic heteroaryl), or phenethyl group, each optionallysubstituted with halo; c) a monocyclic cycloalkyl,—(CH₂)₀₋₁-tetrahydrofuranyl, or —(CH₂)₀₋₁-tetrahydropyranyl group, eachoptionally fused to a phenyl ring, and each optionally substituted withC₁₋₄alkyl or phenyl; or d) an adamantyl group; R² is H, F, methyl, ormethoxy; or R¹ and R² taken together form —(CH₂)₃₋₅— or —(CH₂)₂OCH₂—;and —N(R³)R⁴ is one of the following acyclic, monocyclic, spirocyclic,bridged, or fused ring systems:

where q is 0 or 1; R³ and R⁴ are taken together as defined by thestructure of each one of such moieties; R^(a) is H or OH; R^(b) andR^(c) are each independently H or C₁₋₃alkyl; and each R^(d)substitutuent is methyl or two R^(d) substituents taken together form amethylene or ethylene bridge; provided that when R¹ is methyl, then—N(R³)R⁴ is selected from said spirocyclic, bridged, and fused ringsystems; comprising reacting a chloro-pyrimidine of formula A3:

with a diamine HNR³R⁴.
 2. A method according to claim 1, wherein theR^(b) substituent in diamine HNR³R⁴ is a nitrogen protecting group andsaid reacting provides a compound of formula (Ia):

wherein R¹, R², R³, R⁴, R^(a), R^(c), and R^(d) are as defined forFormula (I), and R^(b) is a nitrogen protecting group.
 3. A methodaccording to claim 2, wherein the R^(b) substituent in diamine HNR³R⁴ istert-butoxycarbonyl.
 4. A method according to claim 2, furthercomprising deprotecting a compound of formula (Ia) to give a compound ofFormula (I) where R^(b) is H.
 5. A method according to claim 1, furthercomprising reacting a hydroxypyrimidine of formula A2:

with POCl₃ to give a compound of formula A3.
 6. A method according toclaim 5, further comprising reacting a β-ketoester of formula A1:

where R is C₁₋₄alkyl; with guanidine or a guanidine salt to give acompound of formula A2.
 7. A method according to claim 6, wherein R ismethyl or ethyl.
 8. A method according to claim 6, wherein saidguanidine salt is guanidine hydrochloride, guanidine carbonate,guanidine nitrate, or guanidine sulfate.
 9. A method according to claim6, wherein said reacting a β-ketoester of formula A1 with guanidine or aguanidine salt is performed in the presence of a base.
 10. A methodaccording to claim 5, wherein said reacting a hydroxypyrimidine offormula A2 with POCl₃ is performed in the presence of at least one of atertiary amine and a tetraalkylammonium chloride salt.
 11. A methodaccording to claim 10, wherein said reacting a hydrosypyrimidine offormula A2 with POCl₃ is performed in the presence of a tertiary amineand a tetraalkylammonium chloride salt.
 12. A method according to claim1, wherein R¹ is C₁₋₆alkyl, and —N(R³)R⁴ is one of the following systems


13. A method according to claim 12, wherein R² is H.